Like James Bond, inflammation is a specialised agent – and a ruthless assassin

Dn-de-de-dn, de-de-de, dun-de-de-dun… Ah, the iconic and ubiquitous Monty Norman-composed James Bond theme. Who doesn’t know and, indeed, love it?

Listen closely and you can also hear its orchestral refrains when activated immune cells fire up an inflammatory response.

That’s because, like James Bond, inflammation is a specialised agent – and ruthless assassin – equipped with a licence to kill, which it uses liberally and often in the manner of a Sean Connery or Daniel Craig.

Unlike 007, however – who is strictly held to account, at least in theory – inflammation carries out its ‘take-no-prisoners’ mandate with virtual impunity and indiscrimination. Indeed, it is without regard to collateral damage according to Machiavellian end-justifies-the-means principles.

When infection is present, the priority is to wipe it out, root and branch, whatever the cost and the consequences, under a brutal inflammatory onslaught – the niceties of selectivity and specificity be damned.

The simplest definition of inflammation is from the Latin – calor, dolor, rubor, tumour.

This concise and nicely assonant phrase refers to the heat (calor), pain (dolor), redness (rubor) and swelling (tumour) that often, but not always, describe the clinical symptoms of inflammation as the Roman encyclopaedist, Aulus Cornelius Celsus (circa 25 BC-circa 50 AD), first observed.

A century and a half later, Galen added a fifth sign: function laesa (loss of function).  Viewed through a modern lens, inflammation is a protective response that eliminates invading pathogens and dead or necrotic cells, as well as repairs damaged tissue.

Key to the inflammatory response is activated immune cells such as monocytes, macrophages, neutrophils, lymphocytes and dendritic cells. Activated immune cells release inflammatory proteins called cytokines and chemokines.

These inflammatory proteins increase blood flow and access of immune cells to the damaged or infected tissues, but potentially at the expense of blood flow to vital organs like the brain, heart, kidneys, lungs and liver, which may damage them and rapidly turn fatal.

In addition to cytokines and chemokines, activated immune cells release a toxic arsenal of oxidants like superoxide, hydroxyl radical, hydroperoxyl radical and nitric oxide.

It also involves proteolytic enzymes like trypsin, which act in concert to damage cell membranes, proteins, and DNA of friend and foe alike.

In some cases, host tissue destruction is so severe as to be life-threatening, which occurs with necrotising fasciitis (NF) from group A Streptococcus, and acute respiratory distress syndrome (ARDS) from SARS-CoV infection, for example.

That said, in the short term, inflammation is usually a lifesaver because it acutely eliminates microbes that otherwise threaten the health and well-being of the organism.

In the long term, however, when inflammation becomes persistent or chronic because of the failure of the inflammatory response to eliminate the cause of injury, it is a lifetaker with a ‘Licence to Kill – and to Ill’.

Whereas acute inflammation starts and resolves rapidly, usually over a few days, when the threat has passed, chronic inflammation starts and resolves slowly, if it resolves at all, over several months to years.

An unresolved acute inflammatory response from persistent injury or infection (e.g., ulcer or SARS-CoV) or chronic exposure to several toxic chemicals such as cigarette smoke gives rise to chronic inflammation.

Unlike acute inflammation, chronic, low-grade inflammation is definitively harmful, almost without exception. It involves a self-escalating, vicious cycle of immune cell recruitment, and release of toxic chemicals, which leads to more and more damage and, ultimately, to more and more inflammation with no to little resolution.

Unsurprisingly, chronic inflammation is thought to be the common denominator behind a whole range of diseases such as heart failure, cirrhosis, fatty liver, pulmonary hypertension, pulmonary fibrosis, depression, chronic obstructive pulmonary disease, type 2 diabetes, neurodegeneration, many cancers and even ageing.

The causes of chronic inflammation are numerous and include persistent infections such as Epstein–Barr virus, hepatitis C virus, human papilloma virus and tuberculosis.

It also takes in external injuries, processed foods that are high in fat, sugar, salt and flavour additives, obesity, physical inactivity, microbiome dysbiosis, tobacco smoking and damage from chemicals or radiation.

Several approved therapies have the potential to prevent and treat diseases of chronic inflammation including antibiotics such as cyclosporine.

There are also antiplatelet therapies like rivaroxaban and antidiabetic agents like the sodium-glucose transporter 2 inhibitor, canagliflozin, and the glucagon-like peptide 1 antagonist, semaglutide (Ozempic).

Other examples include angiotensin-converting enzyme inhibitors (ACE-i) and angiotensin receptor blockers – widely used for the treatment of hypertension – and the biotherapeutic inflammatory cytokine blockers, anakinra, canakinumab and rilonacept for interleukin-1.

In addition, there are tocilizumab for interleukin-6, the cholesterol-lowering statin drugs and the gout-lowering drug, colchicine. These options are often associated with several dose-limiting side effects.

An up-and-coming treatment option for diseases of chronic inflammation is the use of NLRP3 inflammasome inhibitors.

These are agents that directly or indirectly block activation of the NLRP3 inflammasome, a collection of three proteins that when assembled initiate, amplify and sustain the inflammatory response.

Several direct NLRP3 inhibitors – of which the most clinically advanced are the small molecules, RRx-001 (nibrozetone) from EpicentRx and dapansutrile from Olatec – have entered clinical trials for the treatment of various diseases including cancer, endometriosis and heart failure.

So far, these direct NLRP3 inhibitors have not been associated with dose-limiting toxicities unlike the already approved anti-inflammatory agents discussed above.
Potential alternative treatments with a paucity of evidence for their efficacy include vitamins like A, C, E and B, plant-based, fibre rich diets, ketogenic diets, intermittent fasting and exercise.

It’s important to note that chronic mental stress is also a cause of chronic inflammation, so, in place of the tense James Bond theme from the intro, I would instead prescribe Jimmy Buffett’s breezy Caribbean-lifestyle album, License to Chill.

Bryan Oronsky is Chief Medical Officer at EpicentRx. Go to epicentrx.com