Acute Kidney Injury Induced Lupus Exacerbation Through the Enhanced Neutrophil Extracellular Traps (and Apoptosis) in Fcgr2b Deficient Lupus Mice With Renal Ischemia Reperfusion Injury.

Awirut Chareonsappakit,Pornpimol Phuengmaung,Kanyarat Udompornpitak,Asada Leelahavanichkul,Direkrit Chiewchengchol,Prapaporn Pisitkun,Thansita Bhunyakarnjanarat,Supichcha Saithong,Wilasinee Saisorn,Peerapat Visitchanakun

doi:10.3389/fimmu.2021.669162

Awirut Chareonsappakit, Pornpimol Phuengmaung + Show 8 more

Open Access

https://doi.org/10.3389/fimmu.2021.669162

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Abstract

Renal ischemia is the most common cause of acute kidney injury (AKI) that might be exacerbate lupus activity through neutrophil extracellular traps (NETs) and apoptosis. Here, the renal ischemia reperfusion injury (I/R) was performed in Fc gamma receptor 2b deficient (Fcgr2b-/-) lupus mice and the in vitro experiments. At 24 h post-renal I/R injury, NETs in peripheral blood neutrophils and in kidneys were detected using myeloperoxidase (MPO), neutrophil elastase (NE) and citrullinated histone H3 (CitH3), as well as kidney apoptosis (activating caspase-3), which were prominent in Fcgr2b-/- mice more compared to wild-type (WT). After 120 h renal-I/R injury, renal NETs (using MPO and NE) were non-detectable, whereas glomerular immunoglobulin (Ig) deposition and serum anti-dsDNA were increased in Fcgr2b-/- mice. These results imply that renal NETs at 24 h post-renal I/R exacerbated the lupus nephritis at 120 h post-renal I/R injury in Fcgr2b-/- lupus mice. Furthermore, a Syk inhibitor attenuated NETs, that activated by phorbol myristate acetate (PMA; a NETs activator) or lipopolysaccharide (LPS; a potent inflammatory stimulator), more prominently in Fcgr2b-/- neutrophils than the WT cells as determined by dsDNA, PAD4 and MPO. In addition, the inhibitors against Syk and PAD4 attenuated lupus characteristics (serum creatinine, proteinuria, and anti-dsDNA) in Fcgr2b-/- mice at 120 h post-renal I/R injury. In conclusion, renal I/R in Fcgr2b-/- mice induced lupus exacerbation at 120 h post-I/R injury partly because Syk-enhanced renal NETs led to apoptosis-induced anti-dsDNA, which was attenuated by a Syk inhibitor.

Highlights

Prevalence of the dysfunction polymorphism in Fc gamma receptor 2b (Fcgr2b), which is the only one inhibitory receptor in Fc gamma receptor (FcgR) family [1,2,3], is usually found in Asian population
The renal I/R induced the renal excretory dysfunction at 24 h post-renal I/R of Fcgr2b-/- mice was similar to those of wild type (WT) mice, there was higher neutrophil extracellular traps (NETs) and apoptosis in glomeruli which led to lupus nephritis possibly through spleen tyrosine kinase (Syk) signaling after 120 h post-I/R
Similar Organ Injury but More Prominent Neutrophil Extracellular Traps (NETs) and Glomerular Apoptosis at 24 h Post-Renal I/R in Fcgr2b-/- Lupus Mice Compared With WT

Summary

Introduction

Prevalence of the dysfunction polymorphism in Fc gamma receptor 2b (Fcgr2b), which is the only one inhibitory receptor in Fc gamma receptor (FcgR) family [1,2,3], is usually found in Asian population. Fcgr2b is associated with systemic lupus erythematosus (SLE), a common autoimmune disease mostly associated with anti-dsDNA [4]. Deficiency of the inhibitory Fcgr2b signaling causes SLE through the increased antibody production by hyper-reactive B cells [5], whereas Fcgr2b deficiency enhances the protection against malarial infection. Fcgr2b-/mice develop age-dependent lupus characteristics, including asymptomatic lupus prone (less than 16 weeks old), asymptomatic lupus with anti-dsDNA (16-24 weeks old) and full-blown lupus (40 weeks old), which have been used as a representative model of lupus [8]. The hyperresponsiveness of Fcgr2b-/- mice against several pathogen molecules, including pneumococcal antigens and lipopolysaccharide (LPS), has been demonstrated [2, 7, 8], studies on Fcgr2b-/- neutrophils are still very limited. Lupus exacerbation is well-known for neutrophil apoptosis and neutrophil extracellular traps (NETs)-induced cell death (NETosis) [9, 10]

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