Katz B, Zaguri R, Edvardson S
… +10 more, Maayan C, Elpeleg O, Lev S, Davidson E, Peters M, Kfir-Erenfeld S, Berger E, Ghazalin S, Binshtok AM, Minke B
J Clin Invest
· 2026 Apr · PMID 41919504
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Paschalis A, Figueiredo I, Bogdan D
… +21 more, Lundberg A, Santos R, Gurel B, Taha T, Longoria O, Ferreira A, Bertan C, Brittain N, Nelson R, Walker L, Neeb A, Welti J, Yuan W, Mitsopoulos C, Plymate SR, Haffner MC, Sowalsky AG, Carreira S, Sharp A, Gaughan L, de Bono J
J Clin Invest
· 2026 Apr · PMID 41919503
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New androgen receptor (AR) pathway inhibitors (ARPIs) in clinical development, including AR degraders and CYP11A inhibitors, largely target ligand-dependent AR activation and have reported antitumor activity in metastati...New androgen receptor (AR) pathway inhibitors (ARPIs) in clinical development, including AR degraders and CYP11A inhibitors, largely target ligand-dependent AR activation and have reported antitumor activity in metastatic castration-resistant prostate cancer (mCRPC) resistant to established ARPIs, predominately against tumors with AR mutations. We hypothesized that AR-mutated mCRPC exhibits lower AR splice variant 7 (AR-V7) expression and remains full-length-AR (FL-AR) driven, explaining, in part, the antitumor activity of these AR ligand-binding domain (LBD) targeting drugs. The data herein demonstrate that mCRPC tissue biopsies with detectable AR mutations express significantly lower levels of AR-V7 protein and associate with better overall survival and enhanced sensitivity to ARPIs. This is independent of differences in the total number of global splicing events but may be related to differences in splicing factor expression between AR-mutated and nonmutated mCRPC. In conclusion, AR-mutated mCRPC frequently exhibits low AR-V7 expression, arguably explaining the enhanced sensitivity to ARPIs observed in these cancers. Consequently, AR mutation status may serve as a biomarker to predict response to AR-directed therapies.
Ma X, Nettleford SK, Tian Y
… +18 more, Dawany N, Kondo A, Li Y, Maurer K, Karakasheva TA, Shraim R, Williams PA, Parham LR, Simon LA, Danan CH, Conrad MA, Piccoli DA, Devoto M, Romberg N, Sullivan KE, Kaestner KH, Kelsen JR, Hamilton KE
J Clin Invest
· 2026 Apr · PMID 41919502
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Cytokines mediating epithelial and immune cell interactions modulate mucosal healing-a process that goes awry with chronic inflammation as in inflammatory bowel disease. TNFSF13 is a cytokine important for B cell maturat...Cytokines mediating epithelial and immune cell interactions modulate mucosal healing-a process that goes awry with chronic inflammation as in inflammatory bowel disease. TNFSF13 is a cytokine important for B cell maturation and function, but roles for epithelial TNFSF13 and putative contribution to inflammatory bowel disease are poorly understood. We evaluated functional consequences of a novel monoallelic TNFSF13 variant using biopsies, tissue-derived colonoids and induced pluripotent stem cell (iPSC)-derived colon organoids. TNFSF13 variant colonoids exhibited a >50% reduction in secreted TNFSF13, increased epithelial proliferation, and reduced apoptosis, which was confirmed in iPSC-derived colon organoids. Single cell RNA-sequencing and flow cytometry suggested FAS as the predominant colonic epithelial receptor for TNFSF13, which was confirmed by co-immunoprecipitation and binding assays. Imaging mass cytometry revealed an increase in epithelial-associated B cells in TNFSF13 variant colon tissue sections. Finally, TNFSF13 variant colonoids co-cultured with memory B cells demonstrated a reduction in immunoglobulin-producing plasma cells compared to control colonoid cocultures. Our findings support a role for epithelial TNFSF13 as a regulator of colonic epithelial growth and epithelial crosstalk with B cells.
Coll-Tané M, Eidhof I, Han J
… +12 more, Raun N, van Renssen LV, Fisher SE, Kayser MS, Kleefstra T, Pillen S, Hudac CM, Mayneris-Perxachs J, Klein M, Koene S, Castells-Nobau A, Schenck A
J Clin Invest
· 2026 Apr · PMID 41919501
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Sleep disturbances are among the most prevalent clinical features of FOXP1 syndrome, yet their nature and underlying mechanisms remain unclear. Here, we report that individuals with FOXP1 syndrome suffer from insomnia wi...Sleep disturbances are among the most prevalent clinical features of FOXP1 syndrome, yet their nature and underlying mechanisms remain unclear. Here, we report that individuals with FOXP1 syndrome suffer from insomnia with sleep maintenance problems and early waking. Consistently, common variants in FOXP genes were associated with insomnia symptoms and short sleep. These sleep disturbances were recapitulated in Drosophila FoxP mutants, which exhibit severely fragmented and reduced sleep. FoxP loss also led to circadian arrhythmicity and impaired the plasticity of neuropeptide pigment dispersing factor-secreting (PDF-secreting) neurons in a non-cell-autonomous manner. FoxP was required during development for adult sleep integrity, particularly in peptidergic neurons. Transcriptomic analyses revealed a dysregulation of genes involved in peptidergic signaling, including hugin. FoxP was expressed in hugin+ neurons (afferent to PDF-secreting neurons) during development, and its knockdown in these cells was sufficient to induce sleep fragmentation. Our findings establish an evolutionarily conserved role for FOXP proteins in the peptidergic regulation of sleep.
Brittain N, Paschalis A, Nelson R
… +16 more, Adamson B, Walker L, Duncan R, Smith GR, McGill S, Burchmore RJ, Bogdan D, Jiménez-Vacas JM, Welti J, Yuan W, Robson CN, Rescigno P, Luzzi S, Sharp A, de Bono J, Gaughan L
J Clin Invest
· 2026 Apr · PMID 41919500
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Treatment of locally advanced and metastatic prostate cancer (PC) with androgen receptor-targeting (AR-targeting) therapies has limited durability, with disease eventually progressing to castrate-resistant PC (CRPC). Con...Treatment of locally advanced and metastatic prostate cancer (PC) with androgen receptor-targeting (AR-targeting) therapies has limited durability, with disease eventually progressing to castrate-resistant PC (CRPC). Constitutively active AR splice variants (AR-Vs), such as AR-V7, play a key role in driving treatment resistance and disease progression. Importantly, the failure to attenuate AR-V function represents a major unmet clinical need, and as such, defining how AR-Vs are generated is likely to yield new therapeutic targets. Our knowledge of factors that mediate splicing of AR-V-encoding mRNAs remains limited. Here, we have employed an RNA-targeting CasRx approach to identify selective protein interactors of AR-V7 mRNA in PC. TRA2B and its ortholog, TRA2A, were identified as splicing regulators of AR transcripts that facilitate AR-V synthesis at the expense of full-length AR isoforms. TRA2B expression correlated with AR-V7 transcript in CRPC and attenuation of TRA2-mediated splicing diminished PC cell growth. Exploiting TRA2B function may therefore provide new therapeutic opportunities in advanced disease.
J Clin Invest
· 2026 Apr · PMID 41919499
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Cellular senescence in osteogenic mesenchymal cells contributes to age-related bone loss. The bone marrow hosts myeloid cells, the precursors of immune cells, as well as mesenchymal cells, which give rise to osteoblasts...Cellular senescence in osteogenic mesenchymal cells contributes to age-related bone loss. The bone marrow hosts myeloid cells, the precursors of immune cells, as well as mesenchymal cells, which give rise to osteoblasts and osteocytes. The senotype and senolytic response of bone marrow cells, particularly hematopoietic cells, in age-related bone loss is unclear. In this issue, Doolittle et al. showed that of all immune cells, myeloid cells had the strongest senescence profile, yet the relative level of senescence remained lower than that of mesenchymal stromal cells. Mesenchymal cells displayed a profound senotype, rendering them susceptible to senolytic clearance protecting against bone loss. By contrast, selective clearance of p16+ myeloid cells was not long-lasting and, hence, did not fully protect against age-related bone loss. These findings underscore the challenges of developing senolytic strategies for tissues with mixed senotypes, such as bone.
J Clin Invest
· 2026 Apr · PMID 41919497
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Recent advances in genomic technologies have greatly enhanced our understanding of neurodegeneration. Techniques like whole-genome sequencing, long-read sequencing, and large-scale population studies have expanded the ra...Recent advances in genomic technologies have greatly enhanced our understanding of neurodegeneration. Techniques like whole-genome sequencing, long-read sequencing, and large-scale population studies have expanded the range of identified genetic risk factors, uncovering new disease mechanisms and biological pathways that could serve as therapeutic targets. However, translating these genetic insights into clinical practice remains difficult because of challenges in interpreting variants and the limited functional validation of new discoveries. This Review highlights the key genomic technologies advancing diagnosis and research in neurodegeneration. We focus on improvements in variant classification, detection of structural variants and repeat expansions, and combining transcriptomic, proteomic, and functional data to better determine variant pathogenicity. The ongoing integration of genomics, molecular neurobiology, and data science offers great potential for more accurate, biologically informed diagnosis and treatment of neurodegenerative disorders.
J Clin Invest
· 2026 Apr · PMID 41919496
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Crohn's disease can occur anywhere along the small and/or large intestines, but most commonly occurs in the terminal ileum or ascending colon. Factors governing this region-specific inflammation are poorly understood. In...Crohn's disease can occur anywhere along the small and/or large intestines, but most commonly occurs in the terminal ileum or ascending colon. Factors governing this region-specific inflammation are poorly understood. In this issue of the JCI, Spencer et al. used a TNF-driven mouse model of small intestinal Crohn's disease to identify a specific bacterial pathobiont, Chlamydia muridarum, as a necessary and sufficient driver of region-restricted inflammation. C. muridarum triggered increased goblet cell expression of indoleamine 2,3-dioxygenase 1 (IDO1) in the mouse proximal colon, analogous to the human ascending colon. IDO1 metabolism of tryptophan stimulated increased levels of kyneurine, and suppression of this IDO1/kyneurine axis alleviated C. muridarum-provoked inflammation in the proximal colon but not the terminal ileum. Analysis of scRNA-seq datasets from patients with Crohn's disease with ascending colon involvement also supported increased IDO1 expression in a subpopulation of crypt surface epithelial cells. The study highlights a process by which bacterial pathobionts promote region-specific intestinal inflammation.
J Clin Invest
· 2026 Apr · PMID 41919495
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Lysosomes function as metabolic control centers that integrate degradation, nutrient sensing, and stress signaling. In neurons, which must maintain proteostasis and energetic balance throughout life, lysosomal homeostasi...Lysosomes function as metabolic control centers that integrate degradation, nutrient sensing, and stress signaling. In neurons, which must maintain proteostasis and energetic balance throughout life, lysosomal homeostasis determines cellular resilience. Emerging evidence identifies lysosomal injury and defective repair as common denominators across neurodegenerative diseases. Damage to the lysosomal membrane caused by oxidative stress, lipid imbalance, or genetic mutations triggers a hierarchical quality control cascade. Early lesions recruit the endosomal sorting complex required for transport (ESCRT) machinery for mechanical resealing, while larger ruptures activate lipid-centered recovery modules. When repair fails, lysophagy eliminates irreparable organelles and a TFEB-dependent transcriptional program regenerates the lysosomal pool. These tightly coupled responses safeguard neurons from catastrophic proteostatic collapse. Their impairment, through mutations in lysosomal proteins, or through aging, produces the lysosomal fragility that underlies Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis/frontotemporal dementia, and Huntington disease. Crosstalk between lysosomes, mitochondria, and ER integrates local damage with systemic metabolic adaptation, while dysregulated lysosomal exocytosis and inflammation propagate pathology. Understanding how ESCRT complexes, lipid transport, and transcriptional renewal cooperate to preserve lysosomal integrity reveals unifying principles of neurodegeneration and defines molecular targets for intervention. Restoring lysosomal repair and renewal offers a rational path toward preventing neuronal loss.
J Clin Invest
· 2026 Apr · PMID 41919494
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Alcohol use disorder (AUD) is linked with changes in brain structure and function, with robust evidence for neurodegenerative changes, including synaptic loss in preclinical models. Developing therapeutic strategies to t...Alcohol use disorder (AUD) is linked with changes in brain structure and function, with robust evidence for neurodegenerative changes, including synaptic loss in preclinical models. Developing therapeutic strategies to target synaptic loss will require human studies that clarify their clinical relevance of these changes. In the current issue, Zakiniaeiz et al. demonstrate that AUD and alcohol consumption are associated with lower synaptic vesicle glycoprotein 2a (SV2A) expression, indexed by regional [11C]UCB-J PET. This is, to our knowledge, the first in vivo evidence of relationships between synaptic density and alcohol use, and, as such, it represents an important step toward understanding how AUD influences brain structure and function. Here, we describe two longstanding clinical issues in the AUD population - relapse and dementia risk - and how the results of the present study may guide future investigations of these issues.
Ma Z, Jia W, Zhou X
… +7 more, Liu J, Li Q, Chang R, Shiqi G, Yuan N, Chen Z, Lan P
J Clin Invest
· 2026 May · PMID 41915438
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Epigenetic dysregulation is associated with immune evasion and immune checkpoint blockade (ICB) resistance. Here, using in vivo CRISPR/Cas9 screens targeting epigenetics-related factors in mouse tumor models treated with...Epigenetic dysregulation is associated with immune evasion and immune checkpoint blockade (ICB) resistance. Here, using in vivo CRISPR/Cas9 screens targeting epigenetics-related factors in mouse tumor models treated with ICB, we identified chromobox 4 (CBX4) as a key negative regulator of the immune tumor microenvironment (TME). Single-cell RNA-seq and spatial transcriptomics analyses of patients receiving neoadjuvant anti-programmed cell death protein 1 (anti-PD-1) therapy revealed high CBX4 expression in both tumor cells and immunosuppressive tumor-associated macrophage subpopulations, with preferential accumulation in nonresponders. Deficiency of CBX4 in macrophages or tumor cells induced robust antitumor immunity and increased infiltration and the cytotoxic activity of CD8+ T cells and NK cells, thereby heightening the sensitivity of ICB treatment. Mechanistically, CBX4 targeted H3K9me3- and H3K27me3-marked endogenous retroelements such as RLTR4-Mm-int. Loss of CBX4 derepressed retrotransposons, activating cytosolic RNA-sensing pathways and triggering the type I IFN response, ultimately leading to a robustly inflamed TME. Moreover, we uncovered a negative correlation between CBX4 expression, immune responses, and retrotransposon levels, and were able to determine the prognosis of patients with hepatocellular carcinoma (HCC) undergoing ICB therapy. Our study establishes CBX4 as an epigenetic immune checkpoint through the epigenetic silencing of retrotransposons, remodeling the immune TME and thus providing a promising therapeutic target to enhance tumor immunogenicity and overcome immunotherapy resistance.
Wu Y, Tavares E, Liang B
… +14 more, Wee WB, Mennella V, Feng HC, Cao J, Wong PY, Zheng J, He M, Stephenson KA, Hanan Hochma L, Li JM, Chen NP, Dell SD, Heon E, Liu Z
J Clin Invest
· 2026 May · PMID 41915430
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Cilia are cellular organelles that extrude from the surface of various cell types, serving either sensory or motile functions. Retinitis pigmentosa GTPase regulator (RPGR) variants affect both photoreceptor sensory cilia...Cilia are cellular organelles that extrude from the surface of various cell types, serving either sensory or motile functions. Retinitis pigmentosa GTPase regulator (RPGR) variants affect both photoreceptor sensory cilia and airway motile cilia, leading to retinitis pigmentosa (RP) and primary ciliary dyskinesia (PCD), respectively. Not all patients develop PCD, and it remains unclear which RPGR variants predispose patients to PCD. Here, we leverage 2D organoids, super-resolution microscopy, and live-cell imaging to characterize the multiciliated cells (MCCs) from patients with different RPGR variants and CRISPR-modified RPGR KO MCCs. We demonstrate that MCCs with RPGR variants have reduced ciliation, shorter cilia, impaired cilia beat, or cilia beat incoordination, potentially resulting in compromised mucociliary clearance and lung diseases. Moreover, we show that RPGR regulates motile cilia through interfering with F-actin dynamics, evidenced by the undissolved F-actin meshwork in RPGR-deficient MCCs, and the defects can be ameliorated with either latrunculin A or Y27632 treatment. Though PCD was observed only in patients with variants that affect both isoforms, patients with RPGRORF15 variants also had cilia and airway anomalies. All RPGR variants affected motile cilia in some way, and the mechanisms involved the accumulation of apical F-actin.
Chapman NS, Borisevich V, Kose N
… +9 more, Myers L, Priest S, Bergeron É, Trigo Esteban E, Sánchez-Seco MP, Melero J, Geisbert TW, Cross RW, Crowe JE
J Clin Invest
· 2026 May · PMID 41915428
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Crimean-Congo hemorrhagic fever virus (CCHFV) is an emerging arboviral and zoonotic bunyavirus. CCHFV can infect livestock, wild animals, and humans. Here, we report the isolation of a panel of mAbs from the B cells of a...Crimean-Congo hemorrhagic fever virus (CCHFV) is an emerging arboviral and zoonotic bunyavirus. CCHFV can infect livestock, wild animals, and humans. Here, we report the isolation of a panel of mAbs from the B cells of an immune individual following a natural nosocomial infection. We determined that the panel comprised antibodies that bound to 2 glycoproteins: (a) the carboxy-terminal glycoprotein (Gc) that serves as the fusion protein and (b) the glycoprotein 38 (GP38). By antibody variable gene analysis, we identified genetic diversity in the B cell response to CCHFV within a single donor for both Gc- and GP38-specific responses. Protection against most bunyavirus-associated diseases is mediated principally by neutralizing antibodies, but here, we found that neutralization activity was not associated with protection. Gc-specific antibodies to diverse antigenic sites neutralized only weakly and did not protect against heterologous virus challenge. GP38-specific antibodies bound to 2 dominant antigenic sites on the glycoprotein. Although GP38-specific antibodies did not neutralize the virus, one mediated protection against heterologous virus challenge in an experimental model of infection in mice primarily by complement-mediated activity. These studies support the development of protective CCHFV countermeasures against GP38.
Mendes L, Dutey-Magni PF, Grist E
… +17 more, Sachdeva A, Santos Vidal S, Lall S, Parry MA, Amos CL, Atako N, Wingate A, Wetterskog D, Sydes MR, Parker CC, Clarke N, Sweeney CJ, Parmar MK, Brown LC, James ND, Berney DM, Attard G
J Clin Invest
· 2026 May · PMID 41915426
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<article data-scroll-anchor="false" data-testid="conversation-turn-47" data-turn="user" data-turn-id="be25b520-cadc-4509-8230-4988b5406e4d" dir="auto" tabindex="-1"> Prostate cancers with high proliferation rates have sh...<article data-scroll-anchor="false" data-testid="conversation-turn-47" data-turn="user" data-turn-id="be25b520-cadc-4509-8230-4988b5406e4d" dir="auto" tabindex="-1"> Prostate cancers with high proliferation rates have shorter survival times but when spread has occurred (metastatic), there is increased sensitivity to hormone therapy with abiraterone. </article>.
Sun Z, Torphy RJ, Miller EN
… +18 more, Darehshouri A, Vigil I, Terai T, Eck E, Sun Y, Guo Y, Fykstra DP, Yee EJ, Hu J, Kedl RM, Lasda EL, Hesselberth JR, Siegenthaler JA, MacLean PS, Bruce KD, Randolph GJ, Schulick RD, Zhu Y
J Clin Invest
· 2026 Jun · PMID 41874575
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The lymphatic system plays a central role in lipid absorption by transporting triglyceride-rich particles called chylomicrons (CMs) from the small intestine to the systemic circulation. However, the molecular mechanism b...The lymphatic system plays a central role in lipid absorption by transporting triglyceride-rich particles called chylomicrons (CMs) from the small intestine to the systemic circulation. However, the molecular mechanism by which CMs get into the intestinal lymphatics is unknown. Here, we demonstrated that GPR182, an atypical chemokine receptor in lymphatic endothelial cells, mediates dietary fat absorption. GPR182-KO mice exhibited a selective increase in circulating high-density lipoproteins and are resistant to diet-induced obesity. GPR182 ablation in mice led to poor lipid absorption and thereby a delay in growth during development. GPR182 broadly interacted with and transported lipoproteins. Transmission electron microscopy analysis revealed that, mechanistically, loss of GPR182 prevented CMs from entering the lacteal lumen of the small intestine. Consistent with this, GPR182 blockade with mAbs protected mice from diet-induced obesity and treated existing obesity. Together, our study identifies GPR182 as a lipoprotein receptor that mediates dietary fat absorption and supports GPR182 blockade as a feasible approach to treating obesity and related disorders.
Lin X, Ryoden Y, Suzuki C
… +4 more, Ishikawa H, Sakuragi T, Uchiyama Y, Nagata S
J Clin Invest
· 2026 May · PMID 41874565
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VPS13A is an intracellular lipid transfer protein comprising more than 3,000 amino acids. Mutations in human VPS13A cause VPS13A disease, a neurodegenerative disorder that affects movement and cognition. VPS13A forms a c...VPS13A is an intracellular lipid transfer protein comprising more than 3,000 amino acids. Mutations in human VPS13A cause VPS13A disease, a neurodegenerative disorder that affects movement and cognition. VPS13A forms a complex with the membrane protein XK to mediate ATP-induced phospholipid scrambling in the plasma membrane. Here, we established a mouse cell system expressing full-length mouse VPS13A and examined its interaction with XK. Mutational analysis revealed that VPS13A binds to XK through a C-terminal β-strand that interacts with a β-hairpin in the central region of XK, an interaction essential for scramblase activity. The XK paralog XKR2, which contains a similar β-hairpin structure, also associates with VPS13A and supports phospholipid scrambling. We analyzed 10 mouse VPS13A variants corresponding to human patient mutations and classified them into 4 groups: (a) L67P, I90K, and W2453R, which showed reduced expression; (b) A1091P and M3080R, which were normally expressed but lacked scramblase activity; (c) S1446P, Q2689H, Y2713C, and R3084H, which modestly impaired expression or activity; and (d) I2763R, which altered cell size and disrupted ER independently of XK. These findings define the VPS13A-XK interaction interface, clarify the functional impact of disease-causing mutations, and reveal an unexpected gain-of-function mutation of a VPS13A variant.
Fang J, Simon JM, Wang T
… +13 more, Gao Y, Bi X, Hu L, Liao C, Zhang C, Adachi Y, Zhou J, Liu H, Liang Q, Nathan JA, Mani R, Brugarolas J, Zhang Q
J Clin Invest
· 2026 May · PMID 41874563
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Resistance to HIF-2α inhibitors such as belzutifan underscores the need to better understand how HIF-2α is transcriptionally regulated in clear cell renal cell carcinoma (ccRCC). Here, we uncover a cytokine-driven enhanc...Resistance to HIF-2α inhibitors such as belzutifan underscores the need to better understand how HIF-2α is transcriptionally regulated in clear cell renal cell carcinoma (ccRCC). Here, we uncover a cytokine-driven enhancer mechanism that sustains HIF-2α expression through the JAK1/STAT3 signaling pathway. Using a genome-wide CRISPR screen in von Hippel-Lindau-deficient (VHL-deficient) ccRCC cells, we identified SOCS3 as a key negative regulator of HIF-2α. Mechanistically, loss of SOCS3 activates JAK1/STAT3 signaling, leading to the recruitment of STAT3 to distal enhancers upstream of endothelial PAS domain-containing protein (EPAS1) that physically loop to its promoter to drive HIF-2α transcription. This cytokine-enhancer circuit was recapitulated in samples from patients with ccRCC and functionally validated using CRISPR interference (CRISPRi), which disrupted enhancer-promoter looping and reduced tumor growth in HIF-2α-dependent models. SOCS3 overexpression or pharmacologic inhibition of JAK1/STAT3 markedly suppressed HIF-2α expression and tumor progression both in vitro and in vivo. Unlike prior studies focusing on VHL/HIF occupancy-driven enhancer activation, this work defines a trans-acting cytokine-JAK1/STAT3 pathway that transcriptionally controls EPAS1. Together, these findings reveal a targetable enhancer mechanism that sustains HIF-2α expression and suggest that combined inhibition of JAK1/STAT3 and HIF-2α may overcome therapeutic resistance in kidney cancer.
Salm L, Zwicky SN, Spari D
… +9 more, Yarahmadov T, Siwicki M, Castanheira FVES, Zbinden J, Stroka D, Zindel J, Dufour A, Kubes P, Beldi G
J Clin Invest
· 2026 May · PMID 41871299
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The peritoneal cavity contains a large population of GATA6-expressing large peritoneal macrophages (LPMs), known to support healing of intraabdominal organs. In this study, we aimed to explore their full sphere of influe...The peritoneal cavity contains a large population of GATA6-expressing large peritoneal macrophages (LPMs), known to support healing of intraabdominal organs. In this study, we aimed to explore their full sphere of influence by examining their ability to perform wound healing at distant sites outside the cavity. In a mouse model combining a remote skin injury with peritoneal stimulation we observed a significant acceleration of skin wound healing in response to LPM activation. Tracking GATA6-expressing LPMs, we demonstrated that LPMs do not migrate to distant wound sites following peritoneal activation. Using parabiosis experiments and administration of activated peritoneal contents indicated an important role of molecules secreted by LPMs in remote skin wound healing. More specifically, proteomic and transcriptomic analyses identified fibronectin as a key factor produced by activated LPMs. In fact, depletion of LPMs or genetic knockout of fibronectin in myeloid cells eliminated the enhanced healing effect. These findings highlight the endocrine function of LPMs in systemic tissue repair, challenging the traditional perspective of plasma fibronectin being exclusively liver derived. Our results suggest that LPMs, strategically positioned in the peritoneal cavity, serve as a source of circulating fibronectin, promoting matrix formation and accelerating wound healing at distant sites.
Herbst B, Blair A, Li Y
… +2 more, Jaffee EM, Zheng L
J Clin Invest
· 2026 May · PMID 41855192
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Single-agent anti-PD-1 antibodies are ineffective for pancreatic ductal adenocarcinoma (PDAC) due to the immunosuppressive tumor-microenvironment (TME). KRAS mutations contribute to the inflammatory TME and therapeutic r...Single-agent anti-PD-1 antibodies are ineffective for pancreatic ductal adenocarcinoma (PDAC) due to the immunosuppressive tumor-microenvironment (TME). KRAS mutations contribute to the inflammatory TME and therapeutic resistance by upregulating IL-8 via MAPK pathways. Thus, this study attempted to overcome the resistance to anti-PD-1 antibodies by targeting downstream KRAS-effectors. The study found that the resistance to anti-PD-1 antibodies can be overcome through MEK1/2-inhibition. The combination of anti-PD-1 antibodies and MEK inhibitors displayed antitumor activity in Kras mutated (Krasmut) KPC mouse tumors, but not WT (KrasWT) Panc02 tumors. The combination of anti-PD-1 antibodies and MEK inhibitors induced recruitment of tumor-associated neutrophils (TANs) via CXCR2, an IL-8 receptor, and increased memory CD8+ T cells and IFN-γ production in treatment-sensitive tumors. However, larger tumors still resisted the combination of anti-PD-1 antibody and MEK inhibitor, likely due to hypoxia/necrosis-induced NETosis and associated paucity of CD8+ T cells. The subsequent addition of anti-CXCR2 antibody overcame this resistance by blocking TAN-infiltration to hypoxic/necrotic areas. Consistently, a risk-score based on the NETosis-MAPK signaling interaction is significantly associated with poorer survival in human PDAC. This study thus provides a new venue for overcoming resistance to strategies targeting KRAS signaling.