Role of inflammasome regulation on immune modulators

Inflammatory responses are essential in eliminating harmful substrates from damaged tissue and inducing recovery.Several cytokines participate in and facilitate this response. Certain cytokines such as interleukin(IL)-1β and IL-18 are initially produced in precursor form in response to toll-like receptor(TLR) ligands and undergo maturation by inflammasomes, which are cytosolic multi-protein complexes containing nucleotide-binding oligomerization domain(NOD)-containing protein 2-like receptors(NLRs). Immune modulators targeting inflammasomes have been investigated to control inflammatory diseases such as metabolic syndrome. However, most immune modulators possessing anti-inflammasome properties attenuate production of other cytokines, which are essential for host defense. In this review, we analyzed the effect of anti-inflammasome agents on the production of cytokines which are not regulated by inflammasome and involving in initial immune responses. As a result, the infiammasome inhibitors are put into three categories: non-effector, stimulator, or inhibitor of cytokine production. Even the stimulator of cytokine production ameliorated symptoms resulting from inflammasome activation in mouse models. Thus, we suggest ideal immune modulators targeting inflammasomes in order to enhance cytokine production while inhibiting cytokine maturation.

Poly-gamma-glutamic acid from Bacillus subtilis upregulates pro-inflammatory cytokines while inhibiting NLRP3, NLRC4 and AIM2 inflammasome activation

Poly-gamma-glutamic acid(γ-PGA)is a natural,edible and non-toxic polymer synthesized by Bacillus subtilis and is suggested as a safe biomaterial for the use in hydrogels and vaccine adjuvants.However,the effect ofγ-PGA on inflammasome activation has not yet been studied in macrophages.Inflammasomes,which are intracellular multi-protein complexes,promote acute and chronic inflammation via interleukin-1βor interleukin-18 maturation,and they are known targets for metabolic syndromes and cancer.In this study,we observed thatγ-PGA attenuated NLRP3,NLRC4 and AIM2 inflammasome activation,whereas it upregulated pro-inflammatory cytokine expression in human and murine macrophages.Althoughγ-PGA had conflicting effects on cytokine production and maturation,it clearly alleviated the severity of lipopolysaccharide-induced endotoxin shock in an animal model.Thus,we suggestγ-PGA as a candidate to control inflammasome-mediated disorders.

Retinoic acid enhances lactoferrin-induced IgA responses by increasing betaglycan expression

Lactoferrin （LF） and retinoic acid （RA） are enriched in colostrum, milk, and mucosal tissues. We recently showed that LF-induced IgA class switching through binding to betaglycan （transforming growth factor-beta receptor III, TpRIII） and activation of canonical TGF-p signaling. We investigated the combined effect of LF and RA on the overall IgA response. An increase in IgA production by LF was further augmented by RA. This combination effect was also evident in Ig germ-line α （GLa） transcription and GLa promoter activity, indicating that LF in cooperation with RA increased IgA isotype switching. We subsequently found that RA enhanced TβRIII expression and that this increase contributed to LF-stimulated IgA production. In addition to the IgA response, LF and RA in combination also enhanced the expression of the gut-homing molecules C-C chemokine receptor 9 （CCR9） and a4β7 on B cells. Finally, peroral administration of LF and RA enhanced the frequency of CCR9＋ IgA＋ plasma cells in the lamina propria. Taken together, these results suggest that LF in cooperation with RA can contribute to the establishment of gut IgA responses.