Fire ant stings: From pain to gain — The therapeutic potential of solenopsin

By Warren R. Heymann, MD, FAAD
July 3, 2024
Vol. 6, No. 27

Fire ant stings are nasty. Lesions usually occur on the lower extremities after the disruption of a nest, causing a large number of ants to swarm and attack. The most common presentation is a wheal and flare accompanied by pain and itch. Sterile pustules may develop within the first 24 hours. Significant local reactions > 10 cm in diameter may occur. Anaphylaxis is possible, appearing in those previously stung by an ant or a yellow jacket because its venom is known to cross-react with the solenopsis venom in vitro. Treatment is symptomatic, with topical or systemic steroids, antihistamines, and prevention or treatment of secondary infection. (1)

Fire ants were introduced into the United States in Mobile, Alabama, about 100 years ago. There are two types of fire ants which belong to the Solenopsis species. The first is a red imported fire ant, Solenopsis invicta, and the second is the black imported fire ant, Solenopsis richteri. (1) Although prevalent in the south, climate change may shift the distribution of fire ant stings to higher latitudes, as predicted for the tropical fire ant S. geminate. (2)

McConnell et al. first isolated the fire ant venom from Solenopsis saevissima as an alkaloid (trans-2-methyl-6-n-undecylpiperidine), which they named solenopsin A. (3) According to Kruse et al., “The venom is 95% water-insoluble alkaloid, with the remaining 5% being an aqueous protein solution. It is the alkaloid part of the venom that causes a sterile pustule at the sting site and has cytotoxic and hemolytic properties. The protein portion contains the allergens.” (1)

Despite its pathogenicity, potential beneficial therapeutic uses of the venom include treating malaria (4), Chagas disease (5), and malignancies. Mo et al. assert, “These venoms promote apoptosis, autophagy and lysis of tumor cells by regulating gene expression of tumor cells and cytotoxicity. Inhibition of tumor cell proliferation, adhesion, migration and invasion, inhibition of tumor angiogenesis and other effects to play an anti-tumor role.” (6)

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Focusing on dermatology, topical solenopsin analogs may be potentially valuable in atopic dermatitis (AD) and psoriasis, primarily by restoring impaired barrier function. Solenopsin has a long lipid side chain. Ceramides are generated from lipid precursors and can be degraded by enzymatic hydrolysis or metabolized into sphingosine-1-phosphate (S1P), a mediator of cellular growth, carcinogenesis, and inflammation. Arbiser et al. have synthesized solenopsin ceramide analogs that are incapable of hydrolysis or metabolism to S1P and have demonstrated that these analogs have in vivo efficacy in a well-validated murine model of psoriasis, the KC-Tie2 mouse. Topical solenopsin derivatives normalized cutaneous hyperplasia in this model by decreasing T cell infiltration, interleukin (IL)-22 transcription, reversing the upregulation of calprotectin and Toll-like receptor (TLR) 4 in inflamed skin, and stimulating interleukin (IL)-12 production in skin dendritic cells. (7) S14, a synthetic derivative of ant venom-derived solenopsin, has demonstrated potent anti-inflammatory effects on the OVA murine model of AD by upregulating IL-12 and downregulating IL-4. The upregulation of IL-12 in murine models of both AD and psoriasis suggests that restoration of Th1 immunity may be a non-immunosuppressive method of resolving a wide variety of cutaneous inflammation.

Dermatologists know the benefits and risks of currently available topical therapies for AD and psoriasis — steroids, calcineurin inhibitors, vitamin D analogs. PDE4 inhibitors, aryl hydrocarbon receptor agonists, and JAK inhibitors. As opined by Leyva Castillo et al., “Use of small molecules that modulate cytokine expression is a novel modality for the treatment of inflammatory disease of the skin.” (8) I find it perplexing (but fascinating) that a venom that can cause so much pain and itch can be considered as an anti-inflammatory agent. Further study of topical solenopsin and its congeners is warranted. Should this prove useful, it would take some of the sting away from the fire ant saga.

Point to Remember: The fire ant venom, solenopsin (and its analogs), has demonstrated anti-inflammatory efficacy in mouse models of atopic dermatitis and psoriasis. Further research is necessary to determine its potential in human disease.

Our expert’s viewpoint

Jack L. Arbiser, MD, PhD, FAAD
Thomas J. Lawley Professor of Dermatology, Emeritus
Emory University School of Medicine

When I was a dermatology resident, two clinical questions fascinated me. First, why are most babies born without evident inflammation, but develop inflammation over time? Second, why do AIDS patients develop severe cases of eczema and psoriasis, despite being infected with HIV, which depletes T cells? Where were the inflammatory T cells coming from?

My research has shown that these questions have a common answer. We now have a more sophisticated understanding of T cells. For the practicing dermatologist, Th1 cells mediate contact dermatitis, Th2 cells mediate atopic dermatitis, and Th17 cells mediate psoriasis. While this is an oversimplification, it is useful for the practicing dermatologist.

Our study of ant venom helped us answer these questions. Ant venom contains the small molecule solenopsin and a protein toxin. Solenopsin analogs were initially developed by Dr. Phil Bowen (then at University of Georgia) to spray on ants to trick them that they had already made ant venom. This approach did not work, but the compounds structurally resembled ceramide, an important component of the skin, so we tested them in skin inflammation. We found that they are active in both psoriasis and atopic dermatitis, and in both instances, induced IL-12.

This has many implications for the skin. First, there is a core keratinocyte inflammatory pathway, related to ceramides, which underlies both atopic dermatitis and psoriasis. This core pathway can be targeted. Most humans are usually not born with core keratinocyte inflammation, but it develops over time, and gets biased towards Th2 (atopic dermatitis) or Th17 (psoriasis) by genetic and environmental factors. Patients with advanced AIDS have loss of Th1 immunity and thus Th2 and Th17 immunity goes unchecked by IL-12. Second, IL-12 is the sentinel against Th2 and Th17 inflammation, and this is produced by normal keratinocytes. Loss of IL-12 promotes Th2 and/or Th17 inflammation, and ant venom solenopsin can restore this balance by inducing IL-12. This is how an inflammatory compound can reduce inflammation without immunosuppression. Finally, some of our biologics (ustekinumab) suppress IL-12. While ustekinumab is effective in some psoriasis patients, novel biologics targeting IL-23 alone may be better. Time will tell. Finally, a drug that targets the aberrant production of cytokines may be superior to one that mops up the cytokines once they are released.

1. Kruse B, Anderson J, Simon LV. Fire Ant Bites. 2023 Aug 7. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan–. PMID: 29261949.

2. Lee CM, Lee DS, Kwon TS, Athar M, Park YS. Predicting the Global Distribution of Solenopsis geminata (Hymenoptera: Formicidae) under Climate Change Using the MaxEnt Model. Insects. 2021 Mar 8;12(3):229. doi: 10.3390/insects12030229. PMID: 33800231; PMCID: PMC7998871.

3. Macconnell JG, Blum MS, Fales HM. Alkaloid from fire ant venom: identification and synthesis. Science. 1970 May 15;168(3933):840-1. doi: 10.1126/science.168.3933.840. PMID: 17768919.

4. Kumari J, Sah RK, Mohaideen S NM, Ahmad S, Pati S, Singh S. Studying the Rationale of Fire Ant Sting Therapy Usage by the Tribal Natives of Bastar Revealed Ant Venom-Derived Peptides with Promising Anti-Malarial Activity. Toxins (Basel). 2022 Nov 11;14(11):789. doi: 10.3390/toxins14110789. PMID: 36422964; PMCID: PMC9697016.

5. Silva RCMC, Fox EGP, Gomes FM, Feijó DF, Ramos I, Koeller CM, Costa TFR, Rodrigues NS, Lima AP, Atella GC, Miranda K, Schoijet AC, Alonso GD, de Alcântara Machado E, Heise N. Venom alkaloids against Chagas disease parasite: search for effective therapies. Sci Rep. 2020 Jun 30;10(1):10642. doi: 10.1038/s41598-020-67324-8. PMID: 32606423; PMCID: PMC7327076.

6. Mo Y, Shi Q, Qi G, Chen K. Potential anti-tumor effects of Solenopsis invicta venom. Front Immunol. 2023 May 22;14:1200659. doi: 10.3389/fimmu.2023.1200659. PMID: 37283754; PMCID: PMC10239855.

7. Arbiser JL, Nowak R, Michaels K, Skabytska Y, Biedermann T, Lewis MJ, Bonner MY, Rao S, Gilbert LC, Yusuf N, Karlsson I, Fritz Y, Ward NL. Evidence for biochemical barrier restoration: Topical solenopsin analogs improve inflammation and acanthosis in the KC-Tie2 mouse model of psoriasis. Sci Rep. 2017 Sep 11;7(1):11198. doi: 10.1038/s41598-017-10580-y. PMID: 28894119; PMCID: PMC5593857.

8. Leyva-Castillo JM, Huang C, Baker P, Bacsa J, Geha RS, Arbiser JL. Ant Venom-Based Ceramide Therapy Is Effective Against Atopic Dermatitis In Vivo. J Drugs Dermatol. 2023 Oct 1;22(10):1001-1006. doi: 10.36849/JDD.7308. PMID: 37801525.

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