The NALP1 inflammasome controls cytokine production and nociception in a rat fracture model of complex regional pain syndrome.
Tibia fracture followed by limb immobilization in rats evokes nociceptive and vascular changes resembling complex regional pain syndrome type I (CRPS I). Previously we observed that substance P (SP) and interleukin-1beta (IL-1beta) signaling contribute to chronic regional nociceptive sensitization in this model. It is known that inflammasome multi-protein complexes containing caspase-1 and NALP1 are involved in the activation of the IL-1beta family of pro-nociceptive cytokines expressed in skin and other tissues. Therefore, we hypothesized that SP activated inflammasomes might contribute to mechanical allodynia after fracture. Using this model we observed that: (1) inflammasome components and products NALP1, caspase-1, IL-1beta and IL-18 were present in low levels in normal skin, but expression of all these was strongly up-regulated after fracture, (2) NALP1, caspase-1 and IL-1beta were co-expressed in keratinocytes, and the number of NALP1, caspase-1, and IL-1beta positive cells dramatically increased at 4 weeks post-fracture, (3) LY303870, an NK1 receptor antagonist, effectively blocked fracture-induced up-regulation of activated inflammasome components and cytokines, (4) IL-1beta and IL-18 intraplantar injection induced mechanical allodynia in normal rats, and (5) both a selective caspase-1 inhibitor and an IL-1 receptor antagonist attenuated fracture-induced hindpaw mechanical allodynia. Collectively, these data suggest that NALP1 containing inflammasomes activated by NK1 receptors are expressed in keratinocytes and contribute to post-traumatic regional nociceptive sensitization. These findings highlight the possible importance of neuro-cutaneous signaling and innate immunity mechanisms in the development of CRPS.
Physical Medicine and Rehabilitation Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304, USA.
Wen-Wu
WW
Li
Tian-Zhi
TZ
Guo
Deyong
D
Liang
Xiaoyou
X
Shi
Tzuping
T
Wei
Wade S
WS
Kingery
J David
JD
Clark
D000818:Animals; D018501:Antirheumatic Agents / Q000494:pharmacology; D020170:Caspase 1 / Q000378:metabolism; D053471:Caspases, Initiator / Q000494:pharmacology; D020918:Complex Regional Pain Syndromes / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D050723:Fractures, Bone / Q000150:complications*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D007211:Indoles / Q000494:pharmacology; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology; D015603:Keratinocytes / Q000378:metabolism; D007633:Keratins / Q000378:metabolism; D008297:Male; D020932:Nerve Growth Factor / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000502:physiology*; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D010812:Physical Stimulation; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013373:Substance P / Q000378:metabolism; D013997:Time Factors
C096759:1-(N-(2-methoxybenzyl)acetylamino)-3-(1H-indol-3-yl)-2-(N-(2-(4-(piperidin-1-yl)piperidin-1-yl)acetyl)amino)propane; D018501:Antirheumatic Agents; D016207:Cytokines; D007211:Indoles; D053590:Interleukin 1 Receptor Antagonist Protein; D009419:Nerve Tissue Proteins; C526260:Nlrp1a protein, rat; D010880:Piperidines; D013373:Substance P; D007633:Keratins; D020932:Nerve Growth Factor; D053471:Caspases, Initiator; D020170:Caspase 1