PT  - JOURNAL ARTICLE
AU  - Kaice A. LaFavers
AU  - Chadi Hage
AU  - Varun Gaur
AU  - Radmila Micanovic
AU  - Takashi Hato
AU  - Shehnaz Khan
AU  - Seth Winfree
AU  - Simit Doshi
AU  - Ranjani N. Moorthi
AU  - Homer Twigg
AU  - Xue-Ru Wu
AU  - Pierre C. Dagher
AU  - Edward Srour
AU  - Tarek M. El-Achkar
TI  - The kidney protects against sepsis by producing systemic uromodulin
AID  - 10.1101/2021.01.08.425960
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2021.01.08.425960
4099  - http://biorxiv.org/content/early/2022/05/06/2021.01.08.425960.short
4100  - http://biorxiv.org/content/early/2022/05/06/2021.01.08.425960.full
AB  - Sepsis is a significant cause of mortality in hospitalized patients. Concomitant development of acute kidney injury (AKI) increases sepsis mortality through unclear mechanisms. While electrolyte disturbances and toxic metabolite buildup during AKI could be important, it is possible that the kidney produces a protective molecule lost during sepsis with AKI. We previously demonstrated that systemic Tamm-Horsfall Protein (THP, uromodulin), a kidney-derived protein with immunomodulatory properties, falls in AKI. Using a mouse sepsis model without severe kidney injury, we show that the kidney increases circulating THP by enhancing basolateral release of THP from medullary thick ascending limb cells. In sepsis patients, changes in circulating THP are positively associated with critical illness. THP is also found de novo in injured lungs. Genetic ablation of THP in mice leads to increased mortality and bacterial burden during sepsis. Consistent with the increased bacterial burden, the presence of THP in vitro and in vivo leads macrophages and monocytes to upregulate a transcriptional program promoting cell migration, phagocytosis and chemotaxis and treatment of macrophages with purified THP increases phagocytosis. Rescue of septic THP-/- mice with exogenous systemic THP improves survival. Together, these findings suggest that through releasing THP, the kidney modulates the immune response in sepsis by enhancing mononuclear phagocyte function and systemic THP has therapeutic potential in sepsis.Significance Statement Sepsis is a significant contributor to kidney injury as well as morbidity and mortality worldwide. Specific therapies to improve outcomes in sepsis with kidney injury have largely been limited to symptom management and infectious agent control, in part because it is unclear how kidney injury increases sepsis mortality. This paper describes the identification of Tamm-Horsfall protein, previously known to protect in ischemic models of AKI, as protective in preclinical models of sepsis. It demonstrates how the loss of THP leads to decreased mononuclear phagocyte function and diversity, increased pathogen burden and decreased survival. THP also increases in sepsis without severe kidney injury and concentrates in injured organs. Further study of THP in sepsis could lead to novel sepsis therapeutics.Competing Interest StatementTEA and RM have applied for a patent related to this work titled Modified Tamm-Horsfall Protein and related compositions and methods of use, publication number US 2018/0305420 A1.