Lipopolysaccharide fromRhodobacter sphaeroidesAttenuates Microglia-Mediated Inflammation and Phagocytosis and Directs Regulatory T Cell Response

Abstract

Microglia activation and neuroinflammation are key events during the progression of neurodegenerative disorders. Microglia exhibits toll-like receptors (TLRs), with predominant expression of TLR4, inducing aberrant neuroinflammation and exacerbated neurotoxicity. Studies suggest that microglia initiate infiltration of T cells into the brain that critically influence disease conditions. We report that LPS-Rs, through TLR4 antagonism, significantly inhibit TLR4 mediated inflammatory molecules like IL-1β, IL-6, TNF-α, COX-2, iNOS, and NO. LPS-Rs regulates JNK/p38 MAPKs and p65-NF-κB signaling pathways, which we report as indispensible for LPS induced neuroinflammation. LPS-Rs mitigates microglial phagocytic activity and we are first to report regulatory role of LPS-Rs which blocked microglia mediated inflammation and apoptotic cell death. LPS-Rs significantly inhibits expression of costimulatory molecules CD80, CD86, and CD40. Chemokine receptor, CCR5, and T cell recruitment chemokines, MIP-1α and CCL5, were negatively regulated by LPS-Rs. Furthermore, LPS-Rs significantly inhibited lymphocyte proliferation with skewed regulatory T (Treg) cell response as evidenced by increased FOXP3, IL-10, and TGF-β. Additionally, LPS-Rs serves to induce coordinated immunosuppressive response and confer tolerogenic potential to activated microglia extending neurosupportive microenvironment. TLR4 antagonism can be a strategy providing neuroprotection through regulation of microglia as well as the T cells.

Brucella abortus‐activated microglia induce neuronal death through primary phagocytosis

“…To determine the phagocytosis ability of microglia, the phagocytic uptake of E. coli DH5a (Invitrogen) was measured as described (Gaikwad & Agrawal-Rajput, 2015). Briefly, microglia were infected with B. abortus at different MOI; or treated with HKBA, L-Omp19, or U-Omp19 for 24 hr.…”

Sex differences in innate immunity and its impact on opioid pharmacology

“…COX exists in two isoforms: COX-1, which is constitutively expressed in most cells, and COX-2 which is expressed more selectively in immune macrophages and is upregulated in response to inflammation (Bertolini et al 2002; Hawkey 2001). Importantly, COX-2 is a pro-inflammatory product of TLR4-mediated immune signaling (Cao et al 1997; Czapski et al 2010; Gaikwad and Agrawal-Rajput 2015; Tse et al 2014; Zhang et al 2008). Both preclinical and clinical studies report that co-administration of COX-2 inhibitors (e.g.…”

“…COX exists in two isoforms, COX-1, which is constitutively expressed in most cells, and COX-2, which is expressed more selectively in immune macrophages and is upregulated in response to inflammation (Hawkey, 2001;Bertolini et al, 2002). COX-2 is a proinflammatory product of TLR4-mediated immune signaling (Cao et al, 1997;Zhang et al, 2008;Czapski et al, 2010;Tse et al, 2014;Gaikwad and Agrawal-Rajput, 2015). Both preclinical and clinical studies indicate that coadministration of COX-2 inhibitors (e.g., celecoxib) with morphine significantly potentiates the resulting pain relief in both sexes (Vaughan et al, 1997;Deciga-Campos et al, 2003;Pinardi et al, 2005;Reuben and Ekman, 2005;Aynehchi et al, 2014).…”

The helminth product, ES-62 modulates dendritic cell responses by inducing the selective autophagolysosomal degradation of TLR-transducers, as exemplified by PKCδ

“…Rather, and more like the non-toxic species of LPS from Rhodobacter sphaeroides 1213 or Bacteroides dorei 14, exposure to ES-62 dampens DC responses to challenge with LPS7811. LPS internalises and trafficks TLR4 via a clathrin-dependent endosomal mechanism, initially to couple to the pro-inflammatory TRAM/TRIF signalling pathway and then ultimately, by promoting antigen (Ag)-presentation, to link innate and adaptive responses (reviewed in refs 10 and 11).…”