{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T05:08:08Z","timestamp":1784092088574,"version":"3.55.0"},"reference-count":56,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T00:00:00Z","timestamp":1784073600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Necrotizing enterocolitis (NEC) is a severe multifactorial inflammatory disorder of the preterm intestine for which effective preventive and therapeutic strategies remain limited. Using formula feeding (FF)-associated dysbiosis combined with subsequent viral inflammation, we previously demonstrated that this clinically relevant two-hit strategy induces NEC through a complex mechanism involving the\n                      <jats:italic>Klebsiella oxytoca<\/jats:italic>\n                      -derived metabolite tilivalline (TV) and NK1.1\n                      <jats:bold>\n                        <jats:sup>+<\/jats:sup>\n                      <\/jats:bold>\n                      cells. Here, we investigated whether chemokine-receptor-dependent inflammatory responses associated with inflammatory cell recruitment contribute to NEC pathogenesis and whether pharmacologic blockade of chemokine-receptor signaling attenuates disease progression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>NEC was induced in C57BL\/6 mouse pups using two novel and clinically relevant two-hit models: FF combined with R837-triggered viral inflammation, or TV gavage in dam-fed pups followed by R837 treatment. In some experiments, pups were pretreated subcutaneously with TAK-779, a pharmacologic inhibitor of CCR2\/CCR5\/CXCR3 signaling. NEC-like intestinal injury was assessed by intestinal permeability and histological analysis. RT-qPCR and flow cytometry were used to evaluate chemokine-receptor expression and inflammatory cell infiltration, respectively. A human NEC RNA-seq dataset (E-MTAB-15683) was used to evaluate the expression of chemokine-receptor genes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Following the R837-induced second hit, mouse pups previously subjected to the FF-associated first hit exhibited robust induction of chemokines and chemokine receptors, accompanied by recruitment of inflammatory cells and the development of NEC. TAK-779 markedly reduced the expression of chemokines and their receptors, attenuated inflammatory cell recruitment, and protected against NEC induced by the sequential FF- and viral inflammation-associated two-hit process. Similarly, subjecting BF pups to TV (first hit) followed by R837 treatment (second hit) resulted in heightened expression of chemokines and their receptors, accompanied by NEC development; both effects were prevented by TAK\u2212779 pretreatment. Notably, analysis of human NEC transcriptomic data revealed increased expression of multiple chemokines and chemokine receptors in diseased intestinal tissues.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Our findings demonstrate that chemokine-receptor-dependent inflammatory responses contribute to the propagation of NEC by promoting the accumulation of NK1.1\n                      <jats:sup>+<\/jats:sup>\n                      cells and other inflammatory cells. Pharmacologic inhibition of chemokine-receptor signaling attenuates NEC in clinically relevant experimental two-hit models that recapitulate key features of disease pathogenesis, highlighting these pathways as potential therapeutic targets warranting further investigation.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1830078","type":"journal-article","created":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T04:47:15Z","timestamp":1784090835000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Chemokine-receptor-dependent inflammatory responses contribute to two-hit-induced experimental necrotizing enterocolitis and represent a potential therapeutic target"],"prefix":"10.3389","volume":"17","author":[{"given":"Saravanan","family":"Subramanian","sequence":"first","affiliation":[{"name":"Pediatric Mucosal Inflammation and Regeneration Research Program, Center for 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