New Roles for Innate Immune Response in Acute and Chronic Kidney Injuries (1)
The innate immune system is phylogenetically conserved and is present in almost all multicellular organisms. This first line of defence is performed via germline‐encoded receptors expressed by macrophages, lymphocytes, dendritic cells, monocytes, neutrophils, and natural killer cells, among others. Pattern recognition receptors (PRRs) in the inflammatory response presented in acute and chronic kidney diseases.
Several Toll‐Like Receptor (TLR) were identified and shown to recognize a wide range of pathogen‐associated molecular patterns [including peptidoglycan, lipopolysaccharide (LPS), CpG DNA, and double‐stranded or single‐stranded RNA] derived from microorganisms. TLRs are divided into two categories: those found in the cell surface membrane (TLR‐1, ‐2, ‐4, ‐5, ‐6, ‐10, ‐11, ‐12 and ‐13) and those found primarily on endosome membranes (TLR‐3, ‐7, ‐8 and ‐9). Nod‐like receptors were identified, as a group of cytoplasmic PRRs, to recognize microbial PAMPs and/or endogenous signals of homeostatic disturbance inside the cells. Several NLRs, such as NLRP‐1, ‐2, ‐3 and, ‐4 are involved in the formation of the complex of cytosolic proteins, called inflammasomes.
In a rat model, that gene and protein expression of TLR‐2 and TLR‐4 were upregulated in kidney tissues after reperfusion in ischaemic injury. Urinary and serum IL‐1β and IL‐18 levels have been shown to be a sensitive and early marker of tubular damage due to ATN. Ischaemic and ATN post‐transplantation patients have greatly increased levels of urinary IL‐18, the opposite of patients with pre‐renal ARF and various other acute and chronic glomerular and tubular diseases.
Studies using the CLP (cecal ligation and puncture) model demonstrated that TLR‐2 and TLR‐4 expression were up‐regulated in hepatic and splenic macrophages, as well as in lungs and in liver. In a model of polymicrobial sepsis induced by CLP, TLR‐4 deficient mice showed an increase in neutrophil migration to infectious foco. TLR‐2 knockout mice had lower serum expression of inflammatory cytokines and increased survival rates when compared to wild type mice. C3H/HeJ mice had significantly increased susceptibility to Gram‐negative bacteria in experimental urinary tract infections, a benign form of septic Septic acute kidney injury (AKI). However, MyD88 deficient mice do not develop AKI induced by sepsis. MyD88 deficient mice were resistant to polymicrobial sepsis, while TLR‐2 and TLR‐4 knockout mice were not. TLR‐9 plays an important role in sepsis and sepsis‐induced AKI. The participation of IL‐33 has also been described in experimental sepsis. L‐33 induces recruitment of neutrophils to sites of infection. treatment with IL‐33 reduced mortality in mice subjected to sepsis by CLP in wild type mice, but not in IL‐1RL1 knockout mice, and increased recruitment of neutrophils into the peritoneal cavity in wild type mice.
The progression of kidney disease to renal failure correlates with infiltration of mononuclear immune cells into the tubule‐interstitial compartment. These infiltrates contain macrophages, dendritic cells, and T cells. In addition, mast cells appear as initiators and amplifiers, and they are able to stimulate innate and adaptive immune responses. Mast cells are significant participants in chronic progressive kidney disease, and their presence is associated with function loss and fibrosis.