NOMID is a model disease to study the effect of chronic IL-1β overproduction in organ tissues. The ‘NOMID rash’ is characteristic and presents as red erythematous macular-papular lesions with a neutrophilic dermal infiltrate, perhaps better named “IL-1-mediated neutrophilic dermatosis (IMEND)”. The severity of disease varies widely in the same individual even without treatment 
. Using immunohistochemistry and gene profiling we established a “severity gradient” of skin abnormalities from normal skin. Interestingly, clinically “normal” appearing pre treatment (pre-NL) and post treatment skin (post-NL) had significant differences from normal tissues, by immunohistochemistry and by residual gene expression abnormalities. Residual gene expression profile differences have also been seen in psoriatic skin post treatment 
suggesting that a “sub-clinical” state of inflammation and tissue adaptation can persist.
Immunohistochemical and immunofluorescent staining indicated that a likely source of bioactive IL-1β production in the skin is myeloid cells in LS dermis that contain activated caspase-1, the enzyme that cleaves pro-IL-1β into its active form. The presence of neutrophils is also characteristic of LS skin. Abundant neutrophils in LS are consistent with an increased gene expression for neutrophil defensins α1 and α3 (DEFA1, DEFA3), where they constitute two of the most upregulated genes compared to normal, pre-NL and post-NL skin. Neutrophils are important effector cells in the killing of bacteria and release of cytotoxic granules, but also have the capability to destroy tissue. However, in NOMID, there is preservation of the skin architecture without scarring at any time. Thus, while neutrophils are usually considered to be first-line pro-inflammatory effector cells, it is possible that they may have a dual role in the resolution of inflammation 
. Recent reports have focused on the anti-inflammatory role of neutrophils such as by releasing neutrophil extracellular traps (NETs) 
, or by their response to IL-10 
. The observation that neutrophil laden LS skin can spontaneously revert to a less inflamed tissue state (pre-NL) in untreated NOMID patients could be explained by the short lifespan of neutrophils. In addition, we speculate that neutrophils could instigate negative feed back mechanisms to control inflammatory damage, preserve tissue function, and initiate resolution of inflammation. In fact, the release of α-defensin proteins from neutrophils rendered protection in a murine peritonitis model 
and blocked phagocytosis 
, indicating another mechanism by which they could control inflammation.
Increased IL-17 mRNA and the role of IL-1 in Th17 cell differentiation 
have led to consideration of IL-17 as an important downstream mediator in cutaneous inflammation and neutrophil recruitment 
. However, there are controversial data on the role of IL-17 in CAPS from mouse models, where IL-17 has been described both as either necessary 
, or not required 
, for the recruitment of neutrophils. Our data indicated that despite increased IL-17 mRNA in LS skin compared to normal tissue, there was, a mixed effect on IL-17 signaling (both up and down regulated), and IL-17-responsive keratinocyte genes (as determined by the addition of IL-17 to keratinocytes) were not elevated 
. The increase in SIGIRR expression seen in inflamed tissue may even suppress Th17 cell proliferation 
. In addition, in LS skin, there was downregulation of MHC class I and II genes suggesting reduced antigen presentation. Hence, the dysregulation of IL-17-induced genes and antigen-presentation may present a possible protective mechanism to limit the development of autoimmunity in IL-1 mediated auto-inflammation, a feature that is absent in CAPS patients even in patients with longstanding disease.
Two thirds of all DEGs in LS tissue were downregulated, which suggests inflammation-dependent epigenetic modification. Epigenetic effects, which include DNA methylation, histone modification, increased microRNA expression, and chromatin modifications have been found to induce a state of “LPS tolerance” that was observed upon restimulation of mainly monocytes with LPS and led to decreased cytokine responses 
. Epigenetic modification in inflamed NOMID skin is supported by the following observations: IPA demonstrated downregulation of genes in the DNA methylation
and Transcriptional repression and polyadenylation
pathway; enzymes modifying histones and histone genes were differentially regulated in LS skin; and variations were seen across the tissue states for 36 microRNAs and 46 small nucleolar RNAs (Table S1
A model of cellular and gene expression/pathway changes that occur in the different tissue states of IL-1 mediated tissue injury summarizes our data (Fig. S8
). Increased IL-1 production leads to recruitment of inflammatory cells, particularly neutrophils, into the dermis. Gene expression levels for the IL-1 receptor and their downstream signaling molecules, Type I and II cytokine signaling pathways and IFN receptors, are progressively downregulated as the tissue states become more “inflamed”. In contrast, negative regulators such as the anti-inflammatory receptor SIGIRR, SOCS1, SOCS3, and the IL-10-inducible negative regulator Bcl-3, become progressively upregulated in inflamed tissue, suggesting negative feed back loops to downregulate IL-1 mediated signaling 
. The increased expression of genes that allow regulatory macrophages to respond to their environment 
supports the presence of cells whose goal is to induce down-regulatory circuits.
As inflammasome mediated IL-1β production may be involved in causing tissue stress and damage in a number of prevalent human diseases, including Type II diabetes, obesity, and coronary artery disease 
, the understanding of the regulation of the homeostatic pathways that can limit tissue stress and damage and restore tissue homeostasis, may lead to novel treatment strategies that can limit inflammation induced tissue stress and damage, and become a viable option to protect tissue undergoing cytokine induced damage.