Extracellular mitochondrial components as new biomarkers for lupus nephritis.

Major reason for mortality among systemic lupus erythematosus patients is renal failure due to the deposition of immune complexes in the glomeruli. Being a chronic disease with multiple relapses and remissions across the lifespan, it's important to know the degree of nephritis for diagnosis as well as the long-term clinical management of the patients. Currently, renal biopsy is being used as the gold standard to diagnose and define the stages of the disease. However, renal biopsy being invasive only provides a localized picture of nephritis, and has the risk of bleeding. Additionally, it is also cost-intensive. Hence, a reliable, non-invasive biomarker is required for lupus nephritis. This study has evaluated extracellular mitochondrial components, including cell-free mitochondria, and cell-free mitochondrial DNA as probable biomarkers of the degree of nephritis. Both showed a significant correlation with proteinuria and protein-creatinine ratio. Our study substantiates their usage as clinical biomarkers of nephritis upon their validation in a larger cohort of lupus nephritis patients and other forms of nephritis. Although the current data suggest using cell-free mitochondria as a biomarker of lupus nephritis is better than the cell-free mitochondrial DNA.

Azithromycin alters Colony Stimulating Factor-1R (CSF-1R) expression and functional output of murine bone marrow-derived macrophages: A novel report.

Antibiotic treatment may lead to side effects that require mechanistic explanation. We investigated the effect of azithromycin (AZM) treatment on bone marrow-derived macrophage (Mφ) generation, their functional output, and the subsequent effect on bacterial clearance in a mouse model of S. flexneri infection. To our fascination, AZM increased PU.1, C/EBPß, CSF-1R/pCSF-1R expressions leading to M2-skewed in vitro BMDM generation. Altered Mφ-functions like- phagocytosis, oxidative stress generation, inflammasome-activation, cytokine release, and phenotype (pro-inflammatory-M1, anti-inflammatory-M2) even in the presence of infection were observed with AZM treatment. AZM increased CD206, egr2, arg1 (M2-marker) expression and activity while reducing CD68, inducible nitric oxide (iNOS) expression, and activity (M1-marker) in Mφs during infection. Pro-inflammatory cytokines (TNF-α, IL-12, IL-1ß) were reduced and anti-inflammatory IL-10 release was augmented by AZM-treated-iMφs (aiMφs) along with decreased asc, nlrp3, aim2, nlrp1a, caspase1 expressions, and caspase3 activity signifying that aMφs/aiMφs were primed towards an anti-inflammatory phenotype. Interestingly, CSF-1R blockade increased NO, IL-12, TNF-α, IL-1ß, decreased TGF-ß release, and CD206 expression in aiMφs. T-cell co-stimulatory molecule cd40, cd86, and cd80 expressions were decreased in ai/aM1-Mφs and co-cultured CD8+, CD4+ T-cells had decreased proliferation, t-bet, IFN-γ, IL-17, IL-2 but increased foxp3, TGF-ß, IL-4 which were rescued with CSF-1R blockade. Thus AZM affected Mφ-functions and subsequent T-cell responses independent of its antibacterial actions. This was validated in the balb/c model of S. flexneri infection. We conclude that AZM skewed BMDM generation to anti-inflammatory M2-like via increased CSF-1R expression. This warrants further investigation of AZM-induced altered-Mφ-generation during intracellular infections.