TLR2 dimer-specific ligands selectively activate protein kinase C isoforms in Leishmania infection.

Of the thirteen Toll-like receptors (TLRs) in mice, TLR2 has a unique ability of forming heterodimers with TLR1 and TLR6. Such associations lead to selective cellular signalling and cellular responses such as cytokine expression. One of the signalling intermediates is protein kinase C (PKC); of which, eight isoforms are expressed in macrophages. Leishmania-a protozoan parasite that resides and replicates in macrophages-selectively modulates PKC-α, PKC-ß, PKC-δ and PKC-ζ isoforms in macrophages. As TLR2 plays significant roles in Leishmania infection, we examined whether these PKC isoforms play selective roles in TLR2 signalling and TLR2-induced anti-leishmanial functions. We observed that the TLR2 ligands-Pam3 CSK4 (TLR1/2), PGN (TLR2/2) and FSL (TLR2/6)-differentially phosphorylated and translocated PKC-α, PKC-ß, PKC-δ and PKC-ζ isoforms to cell membrane in uninfected and L. major-infected macrophages. The PKC isoform-specific inhibitors differentially altered IL-10 and IL-12 expression, Th1 and Th2 responses and anti-leishmanial effects in macrophages and in BALB/c mice. While PKC isoforms' inhibitors had insignificant effects on the Pam3CSK4-induced anti-leishmanial functions, PGN-induced pro-leishmanial effects were enhanced by PKC-(α + ß) inhibitors, whereas PKC-(δ + Î¶) inhibitors enhanced the anti-leishmanial effects of FSL. These results indicated that the ligand-induced TLR2 dimerization triggered differential dose-dependent and kinetic profiles of PKC isoform activation and that selective targeting of PKC isoforms using their respective inhibitors in combination significantly modulated TLR2-induced anti-leishmanial functions. To the best of our knowledge, this is the first demonstration of TLR2 dimer signalling through PKC isoforms and TLR2-induced PKC isoform-targeted anti-leishmanial therapy.

Type-1 interferons prolong the lifespan of neutrophils by interfering with members of the apoptotic cascade.

Polymorphonuclear Neutrophils (PMNs) are metabolically highly active phagocytes, present in abundant numbers in the circulation. These active cells take the onus of clearing invading pathogens by crowding at inflammatory sites in huge numbers. Though PMNs are extremely short living and die upon spontaneous apoptosis, extended lifespan has been observed among those cells arrive at the inflammation sites or tackle intracellular infections or face any microbial challenges. The delay/inhibition of spontaneous apoptosis of these short-living cells at the inflammatory core rather helps in combating pathogens. Like many candidates, type-1 interferons (type-1 IFNs) is a group of cytokines predominant at the inflammation site. Although there are some isolated reports, a systematic study is still lacking which addresses the impact of the predominant type of interferon on the spontaneous apoptosis of neutrophils. Here in, we have observed that exposure of these IFNs (IFN-ß, IFN-α & IFN-ω etc) on human neutrophils prevents the degradation of the Bfl1, an important anti-apoptotic partner in the apoptotic cascade. Treatment showed a significant reduction in the release of cytochrome-C in the cytosol, a critical regulator in the intrinsic apoptotic pathway. We also noticed a reduction in the conversion of procaspase -3 to active caspase-3, a crucial executioner caspase towards initiation of apoptosis. Taken together our results show that exposure to interferon interferes with apoptotic pathways of neutrophils and thereby delay its spontaneous apoptosis. These findings would help us further deciphering specific roles if these inflammatory agents are causing any immune-metabolomic changes on PMNs at the inflammatory and infection core.

Neutrophils: Interplay between host defense, cellular metabolism and intracellular infection.

Neutrophils are short-living innate immune cells present in abundance in the circulation and they provide the first line of defense against infection. Microbicidal effector functions of the immune cells are tightly linked with their metabolic state. Overall knowledge of the association of neutrophil defense with cellular metabolism is still elusive. Recent studies have reported that neutrophil metabolism during granulopoiesis is impacted by the homeostatic process of autophagy. Autophagy is a complex process of which the subtype xenophagy, an antimicrobial autophagic process, clears invading pathogens. Neutrophils, being sentinels of innate immunity, encounter microbes and digest them. Studies on neutrophil antimicrobial autophagy process is still in its primeval state and has not been much explored as in other professional phagocytes. However, several obligate-intracellular pathogens are able to subvert the toxic antimicrobial machineries and utilize neutrophils as their final abodes or "Trojan Horses" for further propagation. In this review, we would provide an insight into the relationship between neutrophil microbicidal effector functions emphasizing on selective antimicrobial autophagy and metabolism, highlighting on some successful pathogens which have evolved ways to subvert or exploit this defense.

An Overview of Seasonal Changes in Oxidative Stress and Antioxidant Defence Parameters in Some Invertebrate and Vertebrate Species.

Antioxidant defence system, a highly conserved biochemical mechanism, protects organisms from harmful effects of reactive oxygen species (ROS), a by-product of metabolism. Both invertebrates and vertebrates are unable to modify environmental physical factors such as photoperiod, temperature, salinity, humidity, oxygen content, and food availability as per their requirement. Therefore, they have evolved mechanisms to modulate their metabolic pathways to cope their physiology with changing environmental challenges for survival. Antioxidant defences are one of such biochemical mechanisms. At low concentration, ROS regulates several physiological processes, whereas at higher concentration they are toxic to organisms because they impair cellular functions by oxidizing biomolecules. Seasonal changes in antioxidant defences make species able to maintain their correct ROS titre to take various physiological functions such as hibernation, aestivation, migration, and reproduction against changing environmental physical parameters. In this paper, we have compiled information available in the literature on seasonal variation in antioxidant defence system in various species of invertebrates and vertebrates. The primary objective was to understand the relationship between varied biological phenomena seen in different animal species and conserved antioxidant defence system with respect to seasons.