Phone (Lab): 704.687.8507
Office: Woodward 386A
HONORS, AWARDS AND MEMBERSHIPS
The tachykinin, substance P, mediates a variety of biological effects via high affinity receptors for this neuropeptide (termed neurokinin-1 receptors: NK-1R). As such, NK-1R antagonists have been subjected to extensive research for use in the treatment of a variety of disease conditions, and several of these agents have recently been introduced clinically to prevent postoperative and chemotherapy-induced nausea and vomiting. Importantly, our laboratory has assembled a compelling body of evidence indicating that substance P/NK-1R interactions exacerbate classical inflammation at mucosal sites and within the CNS. As such, the therapeutic targeting of the actions of SP could potentially limit neurogenic or classical inflammation. In addition to its effects on leukocytes, we have demonstrated that substance P exacerbates the inflammatory responses of resident brain cells including microglia and astrocytes to clinically relevant bacterial pathogens including B. burgdorferi, N. meningitidis, and S. pneumoniae via the NK-1R. Furthermore, we have also shown that endogenous substance P/NK-1R interactions are required for maximal inflammation and CNS damage in murine models of meningitis. Interestingly, our data indicate that prophylactic or therapeutic systemic administration of an NK-1R antagonist can markedly attenuate bacterially-induced neuroinflammation in our mouse models. As such
, these data suggest that the NK-1R may represent an important new target in the treatment of potentially lethal CNS inflammation. In collaboration with Dr. Mario Philipp at Tulane University Primate Center, we are currently performing a comprehensive preclinical evaluation of the ability of substance P to augment classical inflammation in isolated primary human CNS cells and a non-human primate model of bacterial meningitis. These studies represent an essential preclinical translational step to evaluate the therapeutic potential of NK-1R antagonists in the treatment of classical CNS inflammation.
Current Project Support:
NIH 2R01NS050325 “Substance P exacerbation of CNS inflammation”, Ian Marriott, PI, 09/30/12-05/31/17.
Microglia and astrocytes are increasingly recognized to play a critical role in the initiation, progression, and/or maintenance of inflammatory host responses to CNS pathogens. Our laboratory has been at the forefront in the study of the mechanisms by which glial cells perceive viral and bacterial pathogens. The innate immune system recognizes a wide spectrum of pathogens without the need for prior exposure and the identification of highly conserved families of proteins that serve as microbial pattern recognition receptors including the Toll-like (TLR), nucleotide-binding oligomerization domain-like (NLR), and retinoic acid inducible gene-I-like (RLR) receptors has shed light on the mechanisms by which this is accomplished. These microbial sensors precipitate the production of inflammatory cytokines and antiviral type I interferons. Hence, activation of cells in this manner can initiate the repertoire of defense mechanisms used by the innate immune system. Microglia and astrocytes can express cell surface and endosomal TLRs. In addition, we have determined that glial cells also express cytosolic sensors for microbial motifs that may be more relevant for the detection of intracellular pathogens. For example, we described the expression by microgl
ia and astrocytes of NOD2, an intracellular receptor for bacterial peptidoglycans, and we demonstrated the essential role played by this molecule in the inflammatory responses of glia to an array of clinically relevant bacterial CNS pathogens. More recently, we discovered that glia also express two members of the RLR family, RIG-I and MDA5, that function as cytosolic sensors for replicative RNA viruses. Furthermore, we subsequently showed that RIG-I plays a critical role in the inflammatory immune responses of primary human astrocytes to a model neurotropic RNA virus. Finally, we described the expression of a cytosolic sensor for double-stranded DNA, DNA-dependent activator of interferon-regulatory factors (DAI), by murine glia. This molecule has been shown to mediate innate immune responses in murine cell lines following the intracellular administration of viral DNA and we showed that DAI expression was critical for maximal inflammatory glial responses to HSV-1 infection, suggesting that this novel cytosolic dsDNA sensor might play a critical role in the detection of replicative DNA viruses by glia.
Osteomyelitis (OM) is a severe infection of bone tissue that is associated with significant morbidity and often leads to
bone resorption, dysfunction, and progressive inflammatory destruction. The Gram-positive organism, Staphylococcus aureus, is the most common causative agent of OM. Despite improvements in prophylaxis and diagnosis this condition is often refractory to current treatment strategies and is recurrent. An explanation for these phenomena may lie in the ability of the causative agents of OM to invade and persist within resident bone cells including osteoblasts (OB). Importantly, our laboratory has demonstrated that isolated OBs utilize members of the TLR and NLR families of innate immune receptors to detect the presence of microbial products. The activation of these sensors precipitates the production of inflammatory cytokines and chemokines, and antigen presenting and co-stimulatory molecules. Consistent with this observation, our in vitro and in vivo studies show that S. aureus provides a potent stimulus for the production of soluble and cell surface molecules by isolated OBs that could play key roles in the initiation and/or progression of inflammatory immune responses, and enhance the activity of bone-resorbing osteoclasts. As such, the production of these mediators by bacterially challenged OBs may significantly contribute to involucrum and sequestrum formation during OM, and the development of damaging inflammatory host responses following infection.
CURRENT LAB MEMBERS
Angelica N. Martins, Ph.D.
Brittany Johnson, Ph.D.