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Beyond persistent neuroinflammation, long-term TBI disrupts peripheral immune homeostasis, increasing susceptibility to infection and organ dysfunction, particularly in older patients. The voltage-gated proton channel Hv1, expressed in microglia and peripheral immune cells, regulates oxidative injury via modulation of NADPH oxidase activity. Yet few animal studies extend long enough to recapitulate the lifelong trajectory of human TBI, leaving the long-term effects of Hv1 deficiency on systemic immune homeostasis unresolved.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    Young adult (3-month-old) male wild-type (WT) and Hv1 knockout (Hv1KO) mice were subjected to a moderate controlled cortical impact (CCI), and survival was monitored for up to 18 months post-injury, with endpoint analyses performed at 21 months of age. After neurological behavioral assessments, spleen, lung, liver, gut, ipsilateral cortex, and blood samples were collected for flow cytometry, qPCR, NanoString nCounter Panels, and\n                    <jats:italic>in vivo<\/jats:italic>\n                    plasma transfer studies.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Hv1 deficiency resulted in significantly increased mortality following TBI, starting at 14 months post-injury, compared with WT\/TBI mice. No significant difference in survival was observed between the two sham groups. At 18 months post-injury, Hv1KO mice exhibited significant weight loss and splenomegaly. qPCR revealed an approximately 30-fold increase of pan-bacterial 16S rRNA levels in the spleens of Hv1KO\/TBI mice, but not in the lungs or liver. Furthermore, chronic TBI in the Hv1KO mice led to a compromised intestinal tight junction and mucus barrier integrity, accompanied by aberrant activation of the cyclic GMP-AMP synthase-stimulator of interferon genes pathway in the spleen. Transcriptomic profiling of the spleen, liver, and lung revealed distinct post-injury immune signatures in Hv1KO mice. In contrast, surviving Hv1KO\/TBI mice showed modest behavioral resilience and a partially neuroprotective cortical transcriptomic profile. Lastly, systemic transfer of plasma from WT\/TBI or Hv1KO donors into na\u00efve young adult mice altered immune responses in the spleen, lung, and brain.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Hv1 plays a critical role in maintaining peripheral immune integrity and antibacterial defense throughout the chronic course of TBI. Despite conferring modest neuroprotection through attenuation of microglial-mediated oxidative stress, Hv1 deficiency exacerbated systemic phagocyte dysfunction and significantly reduced long-term survival.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.07.31.742029","type":"posted-content","created":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T05:15:28Z","timestamp":1785993328000},"source":"Crossref","is-referenced-by-count":0,"title":["Hv1 proton channel is essential for splenic antibacterial defense and immune homeostasis during the chronic phase of traumatic brain injury in male mice"],"prefix":"10.64898","author":[{"given":"Zhuofan","family":"Lei","sequence":"first","affiliation":[{"name":"Department of Anesthesiology & Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, MD 21201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romeesa","family":"Khan","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX 77030, USA"},{"name":"MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology & Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, MD 21201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kavitha","family":"Brunner","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology & Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, MD 21201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cole R","family":"Sebok","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick J","family":"Devlin","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junyun","family":"He","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology & Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, MD 21201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0359-4620","authenticated-orcid":false,"given":"Rodney M.","family":"Ritzel","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology & Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, MD 21201, USA"},{"name":"Department of Neurology, University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX 77030, USA"},{"name":"Center for Neuroimmunology and Glial Biology, Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junfang","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology & Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, MD 21201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026080708550590000_2026.07.31.742029v1.1","doi-asserted-by":"publisher","DOI":"10.3171\/2017.10.jns17352"},{"key":"2026080708550590000_2026.07.31.742029v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/s1474-4422(22)00309-x"},{"key":"2026080708550590000_2026.07.31.742029v1.3","doi-asserted-by":"crossref","unstructured":"Hanscom M , Loane DJ , Shea-Donohue T: Brain-gut axis dysfunction in the pathogenesis of traumatic brain injury. 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