Santos, F. M. | bioRxiv Science

bioRxiv2026

Early Lipid Remodeling During Ischemia Reperfusion Injury Is Associated with Damage- and Protection-Related Lipid Signatures in Acute Kidney Injury.

Acute kidney injury (AKI) secondary to kidney ischemia-reperfusion (IRI) is driven by profound metabolic perturbations that shape oxidative stress, inflammation, and cell death responses. Despite growing evidence of lipid dysregulation in AKI, its biological and mechanistic relevance remains unclear. To address this gap, we performed comprehensive untargeted kidney lipidomics using LC-QTOF-MS to delineate dynamic lipid changes during the acute phase of murine kidney IRI. Integration of lipidomic signatures with kidney gene-expression profiling and curated datamining revealed early activation of lipid pathways associated with injury responses. IRI induced marked lipidomic reprogramming, characterized by a marked accumulation of glycerolipids, including triacylglycerols (TGs) species detected exclusively after injury, together with increased levels of sphingolipids (ceramides, sphingomyelins, and hexosylceramides). Cardiolipins and most glycerophospholipids declined sharply following IRI, whereas specific phosphatidylcholines (PCs) exhibited opposite regulation, consistent with dynamic membrane remodeling. Datamining linked TG accumulation and altered transcriptional regulation of PC metabolism to repair-prone type 1 injured proximal tubular cells, highlighting its role in early tubular injury. Correlation analyses revealed strong associations between glycerolipids/sphingolipids and markers of renal dysfunction and inflammation, identifying TG 54:9 as a candidate for injury biomarker. Conversely, PE 40:6, PI 38:6, together with several lysophosphatidylcholines and ether-linked phospholipids, correlated positively with nephroprotective and antioxidant markers. Together, these patterns delineate two major lipid modules: a damage-associated module and a nephroprotection-associated module. These findings establish lipid remodeling as a central yet underexplored determinant of AKI pathogenesis and underscore lipidomics as a powerful discovery tool for identifying novel biomarkers and mechanistic targets in kidney disease.

pathology↗

bioRxiv2023

Essential role of the CCL2-CCR2 axis in Mayaro virus-induced disease

Mayaro virus (MAYV) is an emerging arbovirus member of the Togaviridae family and Alphavirus genus. MAYV infection causes an acute febrile illness accompanied by persistent polyarthralgia and myalgia. Understanding the mechanisms involved in arthritis caused by alphaviruses is necessary to develop specific therapies. In this work, we investigated the role of the CCL2/CCR2 axis in the pathogenesis of MAYV-induced disease. For this, WT C57BL/6J and CCR2-/- mice were infected with MAYV subcutaneously and evaluated for disease development. MAYV infection induced an acute inflammatory disease in WT mice. The immune response profile was characterized by an increase in the production of inflammatory mediators, such as IL-6, TNF and CCL2. Higher levels of CCL2 at the local and systemic levels, was followed by significant recruitment of CCR2+ macrophages and a cellular response orchestrated by these cells. CCR2-/- mice showed an increase in CXCL-1 levels, followed by a replacement of the macrophage inflammatory infiltrate by neutrophils. Additionally, absence of the CCR2 receptor protected mice from bone loss induced by MAYV. Accordingly, the silencing of CCL2 chemokine expression in vivo and the pharmacological blockade of CCR2 promoted a partial improvement in disease. Cell culture data support the mechanism underlying MAYVs bone pathology in which: i) MAYV infection promoted a pro-osteoclastogenic microenvironment mediated by IL-6, TNF and CCL2 and ii) migration of osteoclast precursors was dependent on the CCR2/CCL2 axis. Overall, these data contribute to the understanding of the pathophysiology of MAYV infection and to the identification future of specific therapeutic targets in MAYV-induced disease. ImportanceThis work demonstrates the role of the CCL2/CCR2 axis in MAYV-induced disease. Infection of WT C57BL/6J and CCR2-/- mice was associated with high levels of CCL2, an important chemoattractant involved in the recruitment of macrophages, the main precursor of osteoclasts. In the absence of the CCR2 receptor there is a mitigation of macrophage migration to the target organs of infection and protection of these mice against bone loss induced by MAYV infection. Much evidence has shown that host immune response factors contribute significantly to the tissue damage associated to alfavirus infections. Thus, this work highlights molecular and cellular targets involved in the pathogenesis of arthritis triggered by MAYV, and identifies novel therapeutic possibilities directed to the host inflammatory response unleashed by MAYV.

cell biology↗