CD5L constraints acute and systemic inflammation and can be a novel potent therapeutic agent against sepsis

Abstract

The global burden of sepsis, with an estimated 49 million cases and 11 million deaths in 2017, often passes unnoticed to the general public even though it is the direct cause of nearly 20% of all deaths worldwide. This unawareness is perhaps due to misconceptions, or miscoding in the reporting of the ultimate causes of death, as in many diseases it is not the actual infectious agent that causes the biggest harm. Rather, it is the uncontrolled inflammation leading to septic shock that is the most menacing manifestation associated with many infections, and becomes deadly serious once it has passed the stage where anti-microbial drugs no longer have any effect to inactivate or destroy the pathogen. Here we show that the combined anti-bacterial and anti-inflammatory properties of the scavenger receptor cysteine-rich (SRCR) protein CD5L contribute to a remarkable therapeutic effect of the protein to fight sepsis, such that when exogenously administered in C57BL/6 mice with induced lethal-grade sepsis, it can be a very effective curative agent to treat this condition. The resistance conferred by CD5L to polybacterial-induced sepsis using the cecal ligation and puncture (CLP) model is consistent with the reported observations that CD5L physically binds and inactivates diverse species and strains of bacteria. Accordingly, our CD5L-knockout mice are significantly more susceptible to experimentally-induced mid-grade CLP than wild-type animals. We show that CD5L is centered on promoting neutrophil recruitment and activation, overall contributing to reducing the bacteria burden of the animals. However, the dramatic susceptibility of CD5L-deficient animals is not necessarily correlated only with pathogen load, as these mice are also extremely susceptible to sterile sepsis induced by nonlethal doses of LPS. Notwithstanding the observed capacity of CD5L to directly bind to a broad range of pathogens, typical of many PRRs, our evidence suggests that the anti-inflammatory properties of the protein are at least as important as its pathogen-binding potential, and can, and should, be explored to treat the deadly inflammation storm that is sepsis.