Inflammation plays a crucial role in both acute pneumonitis and chronic pulmonary fibrosis induced by irradiation. Immune intervention represents a viable approach to alleviate damages associated with radiation-induced injury. However to devise a successful strategy, it is necessary to understand the roles of key innate immune receptors and sensors during radiation. This understanding is required to for the rational selection of appropriate immune modulators for treating radiation-associated damages. During the last grant period, one of our goals was to focus on key immunologic regulators and their role in radiation-induced damage. These regulators included (a) MyD88 (myeloid differentiation factor 88), the common adaptor molecule for Toll-like receptors (TLR) and (b) NLRP3, a member of the NBD-LRR (NLR) gene family that is now recognized as a key component of the inflammasome complex that controls caspase-1, IL-1 p and IL-18. The TLR and NLR pathways respectively are considered by some as extracellular and intracellular pattern recognition sensors important in the control of innate immunity and inflammation. In contrast to our initial expectation that MyD88 and NLRP3 would exacerbate inflammation, we and other labs have increasingly found that during tissue injury, both molecules serve as homeostatic factors important for tissue repair. In specific, we found that MyD88 and NLRP3 protect against injury sustained upon radiation damage in the lung, and both gene products are critical for minimizing fibrosis and restoring lung function. This is consistent with reports showing that flagellin, a TLR5 agonist, can protect against pulmonary radiation. These data suggest a paradigm shift in how we should view MyD88 and NLRP3 in the context of pulmonary radiation and suggest that both pathways are beneficial in attenuating the damage caused by radiation injury. Hence therapeutic agents that can activate these pathways might protect against radiation damage. Furthermore, since the TLR and NLR pathways are also required for protect host response during infection, these two molecules might protect against a dual exposure to radiation and infectious microbes associated with pandemic and opportunistic infections. Accordingly the Aims are: (1) to assess the use of non-flagellin TLR and NLR agonists as deliverable therapeutics for pulmonary radiation-induced injury;(2) to assess the mechanisms by which MyD88 and NLRP3 serve as protective factors during pulmonary radiation;and (3) to determine the roles of MyD88 and NLRP3 during dual exposure to radiation and infectious agents of immense public health impact, influenza virus and K. pneumoniae.

Public Health Relevance

Inflammation is a key component of radiation-induced injury. In the past grant period we examined two major innate immune pathways mediated independently by the MyD88 and NLR molecules and unexpectedly found that both are radioprotective. We will explore the mechanism of this protection, and assess agonists that can activate these two pathways for radioprotective effect.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1-KS-I)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Duke University
United States
Zip Code
Linz, Brandon M L; Neely, Crystal J; Kartchner, Laurel B et al. (2017) Innate Immune Cell Recovery Is Positively Regulated by NLRP12 during Emergency Hematopoiesis. J Immunol 198:2426-2433
Racioppi, Luigi; Lento, William; Huang, Wei et al. (2017) Calcium/calmodulin-dependent kinase kinase 2 regulates hematopoietic stem and progenitor cell regeneration. Cell Death Dis 8:e3076
Swanson, Karen V; Junkins, Robert D; Kurkjian, Cathryn J et al. (2017) A noncanonical function of cGAMP in inflammasome priming and activation. J Exp Med 214:3611-3626
Lee, Jaewoo; Jackman, Jennifer G; Kwun, Jean et al. (2017) Nucleic acid scavenging microfiber mesh inhibits trauma-induced inflammation and thrombosis. Biomaterials 120:94-102
Andrews, Rachel N; Metheny-Barlow, Linda J; Peiffer, Ann M et al. (2017) Cerebrovascular Remodeling and Neuroinflammation is a Late Effect of Radiation-Induced Brain Injury in Non-Human Primates. Radiat Res 187:599-611
Chen, Liang; Wilson, Justin E; Koenigsknecht, Mark J et al. (2017) NLRP12 attenuates colon inflammation by maintaining colonic microbial diversity and promoting protective commensal bacterial growth. Nat Immunol 18:541-551
Himburg, Heather A; Doan, Phuong L; Quarmyne, Mamle et al. (2017) Dickkopf-1 promotes hematopoietic regeneration via direct and niche-mediated mechanisms. Nat Med 23:91-99
Jha, Sushmita; Brickey, W June; Ting, Jenny Pan-Yun (2017) Inflammasomes in Myeloid Cells: Warriors Within. Microbiol Spectr 5:
DeBo, Ryne J; Lees, Cynthia J; Dugan, Greg O et al. (2016) Late Effects of Total-Body Gamma Irradiation on Cardiac Structure and Function in Male Rhesus Macaques. Radiat Res 186:55-64
Mont, Stacey; Davies, Sean S; Roberts Second, L Jackson et al. (2016) Accumulation of isolevuglandin-modified protein in normal and fibrotic lung. Sci Rep 6:24919

Showing the most recent 10 out of 188 publications