Early treatment with C-reactive protein-derived peptide reduces septic acute kidney injury in mice via controlled activation of kidney macrophages

Abstract

Acute kidney injury (AKI) remains a high mortality in sepsis and effective therapies based on its pathogenesis remain elusive. Macrophages are crucial for clearing bacteria from vital organs, including the kidney, under septic conditions. Excessive macrophage activation results in organ injury. C-reactive protein (CRP) peptide (174-185), a functional product of proteolyzed CRP in vivo, effectively activates macrophages. We investigated the therapeutic efficacy of synthetic CRP peptide on septic AKI, focusing on effects on kidney macrophages. Mice underwent cecal ligation and puncture (CLP) to induce septic AKI and were intraperitoneally administered 20 mg/kg of synthetic CRP peptide 1 hour post-CLP. Early CRP peptide treatment improved AKI while still clearing infection. Ly6C-negative kidney tissue-resident macrophages did not significantly increase at 3 hours after CLP, while Ly6C-positive monocyte-derived macrophages significantly accumulated in the kidney 3 hours post-CLP. CRP peptide augmented the phagocytic ROS production in both subtypes of kidney macrophage at 3 hours. Interestingly, both subtypes of macrophage increased ROS production 24 hours post-CLP compared to control, while CRP peptide treatment maintained ROS production at the same level seen 3 hours post-CLP. Although bacterium-phagocytic kidney macrophages produced TNF-α, CRP peptide reduced bacterial propagation and tissue TNF-α levels in the septic kidney at 24 hours. Although both subsets of kidney macrophages showed populations of M1 at 24 hours post-CLP, CRP peptide therapy skewed the macrophages population towards M2 at 24 hours. CRP peptide alleviated murine septic AKI via the controlled activation of kidney macrophages and is an excellent candidate for future human therapeutic studies.

Concept and Diagnostic Challenges of Renal-Limited Hemophagocytic Syndrome/Macrophage Activation Syndrome

“…Macrophages in mice are classified into two types based on their phenotype and function: F4/80 low CD11b high monocyte-derived (bone marrow-derived) macrophages with proinflammatory cytokine-producing capacity (e.g., TNF or IL-12), and F4/80 high CD11b low tissue-resident macrophages with phagocytic activity [30]. Recent studies have shown that the kidney contains both types of macrophages (Figure 5) [31,32] and that various disease conditions affect their function and proportion [31,33]. Thus, it seems reasonable that the activation of macrophages and their interaction with cytotoxic lymphocytes occur locally in the kidneys of patients with renal-limited HPS/MAS; however, future research is needed to evaluate this hypothesis.…”

“…tissue-resident macrophages with phagocytic activity [30]. Recent studies have shown that the kidney contains both types of macrophages (Figure 5) [31,32] and that various disease conditions affect their function and proportion [31,33]. Thus, it seems reasonable that the activation of macrophages and their interaction with cytotoxic lymphocytes occur locally in the kidneys of patients with renal-limited HPS/MAS; however, future research is needed to evaluate this hypothesis.…”